2-(1h-indazol-3-yl)-3h-imidazo[4,5-c]pyridines and their anti-inflammatory uses thereof

ABSTRACT

Indazole compounds for treating various diseases and pathologies are provided. More particularly, the use of an indazole compound or analogs thereof, in the treatment of inflammatory diseases or disorders is provided.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.62/252,332, filed Nov. 6, 2015, and 62/303,168, filed Mar. 3, 2016, bothof which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

This disclosure relates to methods for treating diseases or disordersassociated with inflammation. The provided methods includeadministration of an indazole compound, including pharmaceuticallyacceptable salts.

BACKGROUND

Inflammation is the response of body tissues to injury or irritation. Assuch, inflammation is a fundamental, stereotyped complex of cytologicand chemical reactions of affected blood vessels and adjacent tissues inresponse to an injury or abnormal stimulation caused by a physical,chemical or biological agent. Inflammation typically leads to theaccumulation of fluid and blood cells at the site of injury, and isusually a healing process. Inflammation, however, can sometimes causesharm, usually through a dysfunction of the normal progress ofinflammation. Inflammatory diseases are those pertaining to,characterized by, causing, resulting from, or affected by inflammation.

SUMMARY

Provided are compositions and methods for treating inflammatory diseasesor disorders in a subject in need thereof.

Some embodiments disclosed herein include compounds containing anindazole core. Other embodiments disclosed herein include pharmaceuticalcompositions and methods of treatment using these compounds.

One embodiment disclosed herein includes a method of treating a diseaseor disorder associated with inflammation in a subject in need thereof,the method comprising administering to the subject a compound of Formula(I):

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹ is -heteroarylR³R⁴;

R² is selected from the group consisting of H, -heteroarylR⁵,-heterocyclylR⁶ and -arylR⁷;

R³ is selected from the group consisting of H, -heterocyclylR⁸,—NHC(═O)R⁹, NHSO₂R¹⁰, —NR¹¹R¹² and —(C₁₋₆ alkyl)NR¹¹R¹²;

with the proviso that R² and R³ are not both H;

R⁴ is 1-3 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

each R⁵ is independently 1-4 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, —C(═O)R¹¹, aminoand —(C₁₋₆ alkyl)NR¹¹R¹²;

each R⁶ is independently 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

each R⁷ is independently 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, amino, —(C₁₋₆alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆ alkyl)NR¹¹R¹²;

R⁸ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino;

R⁹ is selected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl;

R¹⁰ is selected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷, and -carbocyclylR¹⁴;

each R¹¹ is independently selected from C₁₋₆ alkyl;

each R¹² is independently selected from the group consisting of H andC₁₋₆ alkyl;

each R¹¹ and R¹² are optionally linked to form a five or six memberedheterocyclyl ring;

each R¹³ is independently selected from the group consisting of H andC₁₋₆ alkyl;

R¹⁴ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments of Formula (I):

R¹ is -heteroarylR³R⁴;

R² is -arylR⁷;

R³ is a —NHC(═O)R⁹;

R⁴ is H;

each R⁷ is independently 1-2 substituents each selected from the groupconsisting of halide, —CF₃, —CN, —(C₁₋₆ alkyl)NHSO₂R¹¹, —(C₁₋₆alkyl)NR¹¹R¹², and —NR¹²(C₁₋₆ alkyl)NR¹¹R¹²;

R⁹ is selected from the group consisting of —(C₁₋₆ alkyl), -aryl,-carbocyclyl, and —CH₂carbocyclyl;

each R¹¹ is independently selected from —(C₁₋₆ alkyl);

each R¹² is independently selected from the group consisting of H and—(C₁₋₆ alkyl); and

each R¹¹ and R¹² are optionally linked to form a four to six memberedheterocyclyl ring.

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of Formula (I).

Some embodiments include polymorphs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Non-limiting examples of diseases or disorders which can be treated withthe compounds and compositions provided herein include, withoutlimitation, acne vulgaris, asthma, atherosclerosis, autoimmune diseases,auto inflammatory diseases, cancer-related inflammation, celiac disease,chronic prostatitis, glomerulonephritis, HIV and AIDS,hypersensitivities, leukocyte defects (including but not limited toChediak-Higashi syndrome and chronic granulomatous diseases such astuberculosis, leprosy, sarcoidosis, and silicosis), myopathies, pelvicinflammatory disease, reperfusion injury, rheumatic fever, rheumatoidarthritis, sarcoidosis, transplant rejection, vasculitis, hidradenitisSuppurativa, diverticulitis, interstitial cystitis, lung inflammation,COPD, inflammation post infection, pain, dermatitis, nephritis,amyloidosis, ankylosing spondylitis, chronic bronchitis, scleroderma,lupus, polymyositis, appendicitis, ulcers, Sjogren's syndrome, Reiter'ssyndrome, psoriasis, orbital inflammatory disease, thrombotic disease,and allergic responses to environmental stimuli such as poison ivy,pollen, insect stings and certain foods, including atopic dermatitis andcontact dermatitis.

Also provided herein are methods of decreasing the amount of a biomarkerassociated with an inflammatory disease or disorder in a subject, themethods comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I) as provided herein.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1D are scans of polymorph Form 1 of Compound 10. FIG. 1A is anx-ray powder diffraction scan of fully dried Form 1. FIG. 1B is adifferential scanning calorimetry scan of Form 1. FIG. 1C is a thermalgravimetric analysis scan of Form 1.

FIG. 1D is a dynamic vapor sorption scan of Form 1.

FIGS. 2A-2H are scans of polymorph Forms 2, 2*, and 2** of Compound 10.FIG. 2A is an x-ray powder diffraction scan of fully dried Form 2. FIG.2B is a differential scanning calorimetry scan of Form 2. FIG. 2C is athermal gravimetric analysis scan of Form 2. FIG. 2D is an x-ray powderdiffraction scan of fully dried Form 2*. FIG. 2E is a differentialscanning calorimetry scan of Form 2*. FIG. 2F is a thermal gravimetricanalysis scan of Form 2*. FIG. 2G is an x-ray powder diffraction scan ofForm 2**. FIG. 2H is a differential scanning calorimetry scan of Form2**.

FIGS. 3A-3C are scans of polymorph Form 3 of Compound 10. FIG. 3A is anx-ray powder diffraction scan of fully dried Form 3. FIG. 3B is adifferential scanning calorimetry scan of Form 3. FIG. 3C is a thermalgravimetric analysis scan of Form 3.

FIGS. 4A-4I are scans of polymorph Forms 4, 4*, and 4** of Compound 10.FIG. 4A is an x-ray powder diffraction scan of fully dried Form 4. FIG.4B is a differential scanning calorimetry scan of Form 4. FIG. 4C is athermal gravimetric analysis scan of Form 4. FIG. 4D is an x-ray powderdiffraction scan of fully dried Form 4*. FIG. 4E is a differentialscanning calorimetry scan of Form 4*. FIG. 4F is a thermal gravimetricanalysis scan of Form 4*. FIG. 4G is an x-ray powder diffraction scan ofForm 4**. FIG. 4H is a differential scanning calorimetry scan of Form4**.

FIG. 4I is a thermal gravimetric analysis scan of Form 4**.

FIGS. 5A-5D are scans of polymorph Forms 5 and 5* of Compound 10. FIG.5A is an x-ray powder diffraction scan of fully dried Form 5. FIG. 5B isa differential scanning calorimetry scan of Form 5. FIG. 5C is a thermalgravimetric analysis scan of Form 5. FIG. 5D is an x-ray powderdiffraction scan of Form 5*.

FIGS. 6A and 6B are scans of polymorph Form 6 of Compound 10. FIG. 6A isan x-ray powder diffraction scan of Form 6. FIG. 6B is a differentialscanning calorimetry scan of Form 6.

FIGS. 7A-7C are scans of polymorph Form 7 of Compound 10. FIG. 7A is anx-ray powder diffraction scan of fully dried Form 7. FIG. 7B is adifferential scanning calorimetry scan of Form 7. FIG. 7C is a thermalgravimetric analysis scan of Form 7.

FIGS. 8A-8C are scans of polymorph Form 8 of Compound 10. FIG. 8A is anx-ray powder diffraction scan of fully dried Form 8. FIG. 8B is adifferential scanning calorimetry scan of Form 8. FIG. 8C is a thermalgravimetric analysis scan of Form 8.

FIGS. 9A-9D are scans of polymorph Form 9 of Compound 10. FIG. 9A is anx-ray powder diffraction scan of fully dried Form 9. FIG. 9B is adifferential scanning calorimetry scan of Form 9. FIG. 9C is a thermalgravimetric analysis scan of Form 9. FIG. 9D is a dynamic vapor sorptionscan of Form 9.

FIGS. 10A-10E are scans of polymorph Forms 10 and 10* of Compound 10.FIG. 10A is an x-ray powder diffraction scan of fully dried Form 10.FIG. 10B is a differential scanning calorimetry scan of Form 10. FIG.10C is a thermal gravimetric analysis scan of Form 10. FIG. 10D is anx-ray powder diffraction scan of Form 10*. FIG. 10E is a differentialscanning calorimetry scan of Form 10*.

FIGS. 11A-11F are scans of polymorph Forms 11 and 11* of Compound 10.FIG. 11A is an x-ray powder diffraction scan of fully dried Form 11.FIG. 11B is a differential scanning calorimetry scan of Form 11. FIG.11C is a thermal gravimetric analysis scan of Form 11. FIG. 11D is anx-ray powder diffraction scan of fully dried Form 11*. FIG. 11E is adifferential scanning calorimetry scan of Form 11*. FIG. 11F is athermal gravimetric analysis scan of Form 11*.

FIGS. 12A-12C are scans of Form 12, an example of a non-stoichiometrichydrate of polymorph Form 1 of Compound 10. FIG. 12A is an x-ray powderdiffraction scan of Form 12. FIG. 12B is a differential scanningcalorimetry scan of Form 12. FIG. 12C is a thermal gravimetric analysisscan of Form 12.

FIGS. 13A-13D are scans of Form 13, an example of a non-stoichiometrichydrate of polymorph Form 1 of Compound 10. FIG. 13B is a differentialscanning calorimetry scan of Form 13. FIG. 13C is a thermal gravimetricanalysis scan of Form 13. FIG. 13D is a dynamic vapor sorption scan ofForm 13.

FIGS. 14A-14B show the results of cytokine inhibition studies in humansynovial fibroblasts treated with Compound 10. FIG. 14A provides linegraphs plotting inhibition of IL-6 and TNF-a secretion in human synovialfibroblasts stimulated with IL-113 and treated with Compound 10 for 24hrs as measured by ELISA. FIG. 14B provides bar graphs illustratinginhibition of inflammatory cytokine secretion in human synovialfibroblasts stimulated with IL-1β and treated with Compound 10 for 24hrs as measured by qRT-PCR. n=3, Mean±SEM, *p<0.05, **p<0.01,***p<0.001. Bars from left to right are Unstimulated, IL-1β (100 ng/mL),IL-1β (100 ng/mL)+Compound 10 (100 nM), and IL-1β (100 ng/mL)+Compound10 (30 nM).

FIG. 15 shows the results of cytokine inhibition studies in PeripheralBlood Mononuclear Cells (PMBCs). Specifically, inhibition ofpro-inflammatory cytokine secretion in human PBMCs stimulated withlipopolysaccharide (LPS) and treated with Compound 10 for 24 hrs asmeasured using the MSD platform. n=3, Mean±SEM, *p<0.05, **p<0.01,***p<0.001. Bars from left to right are Unstimulated, LPS (500 ng/mL),LPS (500 ng/mL)+Compound 10 (150 nM).

DETAILED DESCRIPTION 1. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched or straight chain chemicalgroup containing only carbon and hydrogen atoms, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. In someembodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls caninclude multiple fused rings. Carbocyclyls can have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. In some embodiments, carbocyclyl groupsinclude 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group withonly carbon atoms present in the ring backbone and having 5 to 14 ringatoms, such as 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pielectrons shared in a cyclic array; wherein at least one ring in thesystem is aromatic. Aryl groups can either be unsubstituted orsubstituted with one or more substituents. Examples of aryl groupsinclude phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl,and others. In some embodiments, the aryl is phenyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, such as 5, 6, 9, or 10 ringatoms; and having 6, 10, or 14 pi electrons shared in a cyclic array;wherein at least one ring in the system is aromatic, and at least onering in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl groups include thienyl, pyridinyl, furyl,oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl,benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl,indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl,thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, and others. In some embodiments, theheteroaryl is selected from the group consisting of thienyl, pyridinyl,furyl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl.

As used herein, “halo,” “halide,” or “halogen” refer to a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, the halide is achloro, bromo or fluoro radical. For example, the halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched, alkyl, alkenyl or alkynyl, substituted with one ormore chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, ahaloalkyl is a fluoroalkyl, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to 3 carbons in length (e.g., 1 to 2 carbons in length or 1 carbon inlength). The term “haloalkylene” means a diradical variant of haloalkyl,and such diradicals can act as spacers between radicals, other atoms, orbetween a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone, such asbetween 1 and 3 heteroatoms, selected from O, N, and S. Heterocyclylscan include multiple fused rings. Heterocyclyls can be substituted orunsubstituted with one or more substituents. In some embodiments,heterocycles have 5-7 members. In some embodiments, the heterocyclylgroup is a six membered heterocycle that has between one and threeheteroatoms selected from O, N or S. In some embodiments, theheterocyclyl group is a five membered heterocycle that has one or twoheteroatoms selected from O, N, or S. Examples of heterocyclyl groupsinclude azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.In some embodiments, the heterocyclyl group is selected from azetidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single non-aromaticcyclic ring comprising at least one heteroatom in the ring systembackbone. A monocyclic heterocyclyl group can be substituted orunsubstituted with one or more substituents. In some embodiments, amonocyclic heterocycle has 5-7 members. In some embodiments, themonocyclic heterocyclyl group is a six membered monocyclic heterocyclethat has between one and three heteroatoms selected from O, N or S. Insome embodiments, the monocyclic heterocyclyl group is a five memberedmonocyclic heterocycle that has one or two heteroatoms selected from O,N, or S. Examples of monocyclic heterocyclyl groups include azirinyl,aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl,tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Exemplary substituents include, forexample, —(C₁₋₉ alkyl) optionally substituted with one or more ofhydroxyl, —NH₂, —NH(C₁₋₃ alkyl), and —N(C₁₋₃ alkyl)₂; —(C₁₋₉ haloalkyl);a halide; a hydroxyl; a carbonyl, such as —C(O)OR, and —C(O)R; athiocarbonyl, such as —C(S)OR, —C(O)SR, and —C(S)R; —(C₁₋₉ alkoxyl)optionally substituted with one or more of halide, hydroxyl, —NH₂,—NH(C₁₋₃ alkyl), and —N(C₁₋₃ alkyl)₂; —OPO(OH)₂; a phosphonate, such as—PO(OH)₂ and —PO(OR′)₂; —OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″;—C(NR′)R″; a cyano; a nitro; an azido; —SH; —S—R; —OSO₂(OR); asulfonate, such as —SO₂(OH) and —SO₂(OR); —SO₂NR′R″; and —SO₂R; in whicheach occurrence of R, R′ and R″ are independently selected from H;—(C₁₋₉ alkyl); C₆₋₁₀ aryl optionally substituted with from 1-3R′″; 5-10membered heteroaryl having from 1-4 heteroatoms independently selectedfrom N, O, and S and optionally substituted with from 1-3 R′″; C₃₋₇carbocyclyl optionally substituted with from 1-3 R′″; and 3-8 memberedheterocyclyl having from 1-4 heteroatoms independently selected from N,O, and S and optionally substituted with from 1-3 R′″; wherein each R′″is independently selected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), ahalide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′,—C(O)NRR′, and a cyano, in which each occurrence of R and R′ isindependently selected from H and —(C₁₋₆ alkyl). In some embodiments,the substituent is selected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), ahalide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′,—C(O)NRR′, and a cyano, in which each occurrence of R and R′ isindependently selected from H and —(C₁₋₆ alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring,” it is to be understood that a bond is formed betweenthe two groups and can involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

The skilled artisan will recognize that some structures described hereincan be resonance forms or tautomers of compounds that can be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this disclosure, though such resonance forms ortautomers are not represented herein.

The compounds provided herein can encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g., mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “polymorph,” as used herein, refers to crystals of the samemolecule having different physical properties as a result of the orderof the molecules in the crystal lattice. Polymorphs of a single compoundhave one or more different chemical, physical, mechanical, electrical,thermodynamic, and/or biological properties from each other. Differencesin physical properties exhibited by polymorphs can affect pharmaceuticalparameters such as storage stability, compressibility, density(important in composition and product manufacturing), dissolution rates(an important factor in determining bio-availability), solubility,melting point, chemical stability, physical stability, powderflowability, water sorption, compaction, and particle morphology.Differences in stability can result from changes in chemical reactivity(e.g. differential oxidation, such that a dosage form discolors morerapidly when comprised of one polymorph than when comprised of anotherpolymorph) or mechanical changes (e.g., crystal changes on storage as akinetically favored polymorph converts to a thermodynamically morestable polymorph) or both (e.g., one polymorph is more hygroscopic thanthe other). As a result of solubility/dissolution differences, somepolymorphic transitions affect potency and/or toxicity. In addition, thephysical properties of the crystal may be important in processing; forexample, one polymorph might be more likely to form solvates or might bedifficult to filter and wash free of impurities (i.e., particle shapeand size distribution might be different between one polymorph relativeto the other). “Polymorph” does not include amorphous forms of thecompound. As used herein, “amorphous” refers to a non-crystalline formof a compound which may be a solid state form of the compound or asolubilized form of the compound. For example, “amorphous” refers to acompound without a regularly repeating arrangement of molecules orexternal face planes.

The term “anhydrous,” as used herein, refers to a crystal form of thecompound of Formula (I) that has 1% or less by weight water. Forexample, 0.5% or less, 0.25% or less, or 0.1% or less by weight water.

The term “solvate” as used herein refers to a crystalline form of acompound of Formula (I), such as a polymorph form of the compound, wherethe crystal lattice comprises one or more solvents of crystallization.

The term “non-stoichiometric hydrate” refers to a crystalline form of acompound of Formula (I) that comprises water, but wherein variations inthe water content do not cause significant changes to the crystalstructure. In some embodiments, a non-stoichiometric hydrate can referto a crystalline form of a compound of Formula (I) that has channels ornetworks throughout the crystal structure into which water molecules candiffuse. During drying of non-stoichiometric hydrates, a considerableproportion of water can be removed without significantly disturbing thecrystal network, and the crystals can subsequently rehydrate to give theinitial non-stoichiometric hydrated crystalline form. Unlikestoichiometric hydrates, the dehydration and rehydration ofnon-stoichiometric hydrates is not accompanied by a phase transition,and thus all hydration states of a non-stoichiometric hydrate representthe same crystal form. In some embodiments, a non-stoichiometric hydratecan have up to about 20% by weight water, such as, about 20%, about 19%,about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about5%, about 4%, about 3%, about 2%, or greater than 1% water by weight. Insome embodiments, a non-stoichiometric hydrate can have between 1% andabout 20% by weight water, such as between 1% and about 5%, 1% and about10%, 1% and about 15%, about 2% and about 5%, about 2% and about 10%,about 2% and about 15%, about 2% and about 20%, about 5% and about 10%,about 5% and about 15%, about 5% and about 20%, about 10% and about 15%,about 10% and about 20%, or about 15% and about 20% by weight water.

In some embodiments the % water by weight in a crystal form, such as anon-stoichiometric hydrate, is determined by the Karl Fischer titrationmethod. In some embodiments, the crystal form is dried prior to KarlFischer titration.

“Purity,” when used in reference to a composition including a polymorphof a compound of Formula (I), refers to the percentage of one specificpolymorph form relative to another polymorph form or an amorphous formof a compound of Formula (I) in the referenced composition. For example,a composition comprising polymorph Form 1 having a purity of 90% wouldcomprise 90 weight parts Form 1 and 10 weight parts of other polymorphand/or amorphous forms of the compound of Formula (I).

As used herein, a compound or composition is “substantially free of” oneor more other components if the compound or composition contains nosignificant amount of such other components. Such components can includestarting materials, residual solvents, or any other impurities that canresult from the preparation of and/or isolation of the compounds andcompositions provided herein. In some embodiments, a polymorph formprovided herein is substantially free of other polymorph forms. In someembodiments, a particular polymorph of the compound of Formula (I) is“substantially free” of other polymorphs if the particular polymorphconstitutes at least about 95% by weight of the compound of Formula (I)present. In some embodiments, a particular polymorph of the compound ofFormula (I) is “substantially free” of other polymorphs if theparticular polymorph constitutes at least about 97%, about 98%, about99%, or about 99.5% by weight of the compound of Formula (I) present. Incertain embodiments, a particular polymorph of the compound of Formula(I) is “substantially free” of water if the amount of water constitutesno more than about 2%, about 1%, or about 0.5% by weight of thepolymorph.

As used herein, a compound is “substantially present” as a givenpolymorph if at least about 50% by weight of the compound is in the formof that polymorph. In some embodiments, at least about 60% by weight ofthe compound is in the form of that polymorph. In some embodiments, atleast about 70% by weight of the compound is in the form of thatpolymorph. In some embodiments, at least about 80% by weight of thecompound is in the form of that polymorph. In some embodiments, at leastabout 90% by weight of the compound is in the form of that polymorph. Insome embodiments, at least about 95% by weight of the compound is in theform of that polymorph. In some embodiments, at least about 96% byweight of the compound is in the form of that polymorph. In someembodiments, at least about 97% by weight of the compound is in the formof that polymorph. In some embodiments, at least about 98% by weight ofthe compound is in the form of that polymorph. In some embodiments, atleast about 99% by weight of the compound is in the form of thatpolymorph. In some embodiments, at least about 99.5% by weight of thecompound is in the form of that polymorph.

The terms “administration” and “administering” refer to a method ofproviding a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian. The method of administration can vary depending on variousfactors, e.g., the components of the pharmaceutical composition, thesite of the disease, the disease involved, and the severity of thedisease. In some embodiments, the compounds and compositions describedherein are administered to a human.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats, mice,rats, cows, sheep, pigs, goats, and non-human primates, but alsoincludes many other species. In some embodiments, the mammal is a human.

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable diluent,” and “pharmaceutically acceptable excipient” includeany solvents, co-solvents, complexing agents, dispersion media,coatings, isotonic and absorption delaying agents and the like which arenot biologically or otherwise undesirable. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe compounds described herein, its use in the therapeutic compositionsis contemplated. Supplementary active ingredients can also beincorporated into the compositions. In addition, various adjuvants suchas are commonly used in the art can be included. These and other suchcompounds are described in the literature, e.g., in the Merck Index(Merck & Company, Rahway, N.J.). Considerations for the inclusion ofvarious components in pharmaceutical compositions are described, e.g.,in Gilman et al. (Eds.) (2010); Goodman and Gilman's: ThePharmacological Basis of Therapeutics, 12th Ed., The McGraw-HillCompanies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Many such salts are known in the art, forexample, as described in WO 87/05297. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like. Organic bases fromwhich salts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine.

“Patient,” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate, or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound, as provided herein,is an amount that is sufficient to achieve the desired physiologicaleffect and can vary according to the nature and severity of the diseasecondition and the potency of the compound. In some embodiments,“therapeutically effective amount” is also intended to include one ormore of the compounds of Formula (I) in combination with one or moreother agents that are effective in treating the diseases and disordersdescribed herein. The combination of compounds can be a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Advances in Enzyme Regulation (1984) 22:27-55, occurs when the effect ofthe compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. It will be appreciated thatdifferent concentrations can be employed for prophylaxis than fortreatment of an active disease. This amount can further depend upon thepatient's height, weight, sex, age, and medical history. A therapeuticeffect relieves, to some extent, one or more of the symptoms of thedisease.

The term “inflammation,” as used herein, refers to the complexbiological response of tissues (e.g., vascular tissues) of an individualto harmful stimuli, such as pathogens, damaged cells, or irritants, andincludes secretion of cytokines and more particularly of proinflammatorycytokine, i.e., cytokines which are produced predominantly by activatedimmune cells such as microglia and are involved in the amplification ofinflammatory reactions.

The terms “inflammatory disease,” “inflammatory disorder” and “diseaseor disorder associated with inflammation,” as used herein, refer to adisease, disorder, and/or syndrome which exhibits an excessive orunregulated inflammatory response.

As used herein, a “cytokine” is a soluble protein or peptide that isnaturally produced by mammalian cells and that regulates immuneresponses and mediates cell-cell interactions. Cytokines can, eitherunder normal or pathological conditions, modulate the functionalactivities of individual cells and tissues. A “proinflammatory cytokine”is a cytokine that promotes systemic inflammation and is involved in theupregulation of inflammatory reactions.

“Treat,” “treatment,” or “treating,” as used herein, refer toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, ameliorating the underlying metabolic causes ofsymptoms, postponing or preventing the further development of adisorder, and/or reducing the severity of symptoms that will or areexpected to develop.

The terms “inhibit” or “decrease,” when used in reference to the effectof any of the compositions or methods provided herein on the productionof proinflammatory cytokines, refer to at least a small but measurablereduction in proinflammatory cytokine release. In some embodiments, therelease of the proinflammatory cytokine is inhibited by at least about10%, at least about 20%, at least about 25%, at least about 30%, atleast about 40%, at least about 50%, at least about 75%, at least about80%, or at least about 90%, over non-treated controls. Inhibition can beassessed using methods described herein or other methods known in theart. Such decreases in proinflammatory cytokine release can result in areduction of the deleterious effects of the release of proinflammatorycytokines.

“Morphea” as used herein refers to a skin condition wherein discoloredand/or hardened patches appear on the skin (e.g., one or more outerlayers of the skin) resulting from excessive collagen deposition.

“Tendinopathy” as used herein refers to a disease or disorder of atendon characterized by inflammation, deterioration, and/or injury ofthe tendon and/or tissue contacting, near, or associated with thetendon. Tendinopathy includes, for example, inflammation of the tendon(e.g., tendonitis), non-inflammatory degeneration of, for example, thestructure and/or composition of a tendon (e.g., tendinosis),inflammation of the paratenon near or in contact with a tendon (e.g.,paratenonitis), micro-trauma to the tendon, and rupture of the tendon(e.g., acute, chronic, partial and/or complete rupture). The term alsoencompasses tenosynovitis, a tendinopathy of the outer lining of thetendon which occurs in certain tendons such as flexor tendons and theAchilles tendon. Symptoms of tendinopathy include pain at rest, uponpalpation of the tendon, and/or with movement of, for example, thetendon, tissue, joint, or bone near or associated with the tendon; jointstiffness; difficulty moving; weakness of the joint or musclessurrounding the tendon; redness of the skin near the tendon; swelling ofthe tendon and/or of tissue near the tendon; and/or crepitus.

“Tendinitis” as used herein refers to an inflammatory injury to thetendon, characterized by degeneration like that observed in tendinosis,but also accompanied by inflammation of the tendon, vascular disruptionand an inflammatory repair response. Tendinitis is often associated withfibroblastic and myofibroblastic proliferation, as well as hemorrhageand organizing granulation tissue. Generally, tendinitis is referred toby the body part involved, such as Achilles tendinitis (affecting theAchilles tendon), or patellar tendinitis (also known as “jumper's knee,”affecting the patellar tendon), though there are certain exceptions,such as lateral epicondylitis (also known as “tennis elbow,” affectingthe Extensor Carpi Radialis Brevis tendon). Symptoms can vary from achesor pains and local stiffness to a burning sensation surrounding theentire joint around the inflamed tendon. In some cases, tendonitis ischaracterized by swelling, sometimes accompanied by heat and redness;there may also be visible knots surrounding the joint. For manypatients, the pain is usually worse during and after activity, and thetendon and joint area can become stiffer the following day as musclestighten from the movement of the tendon.

“Psoriasis” as used herein refers to an autoimmune disease in which skincells build up and causes raised, red, scaly patches to appear on theskin.

“Dermatitis” (also known as eczema) as used herein refers to genericinflammation of the skin. Specific types of dermatitis include atopic,contact, nummular, photo-induced, and stasis dermatitis. These diseasesare characterized by itchiness, red skin, and a rash.

2. Compounds

The compounds and compositions described herein can be used for treatingdiseases or disorders associated with inflammation. In some embodiments,the compounds and compositions described herein act as anti-inflammatoryagents. In some embodiments, the compounds can be used as inhibitors ofone or more proinflammatory cytokines. In some embodiments, theproinflammatory cytokine is selected from the group consisting of IL-1α,IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL23p40, IL-13,IL-15, IL-16, IL-17A, IL-17F, IL-21, IL-23, TNFα, TNF-β, IFN-γ, CXCL1,CD38, CD40, CD69, IgG, IP-10, L-17A, MCP-1, PGE2, sIL-2, and sIL-6.

Provided herein are compounds of Formula (I):

including pharmaceutically acceptable salts thereof.

In some embodiments, R¹ is -heteroarylR³R⁴.

In some embodiments, R² is selected from the group consisting of H,-heteroarylR⁵, -heterocyclylR⁶ and -arylR⁷.

In some embodiments, R³ is selected from the group consisting of H,-heterocyclylR⁸, —NHC(═O)R⁹, —NHSO₂R¹⁰, —NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹².

In some embodiments, there is the proviso that R² and R³ are not both H.

In some embodiments, R⁴ is 1-3 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, each R⁵ is independently 1-4 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³, —C(═O)R¹¹, amino and —(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, each R⁶ is independently 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³ and amino.

In some embodiments, each R⁷ is independently 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³, amino, —(C₁₋₆ alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹².

In some embodiments, R⁸ is 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, R⁹ is selected from the group consisting of C₁₋₉alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl.

In some embodiments, R¹⁰ is selected from the group consisting of C₁₋₉alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷, and -carbocyclylR¹⁴.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl.

In some embodiments, each R¹² is independently selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments, each R¹¹ and R¹² are optionally linked to form afive or six membered heterocyclyl ring.

In some embodiments, each R¹³ is independently selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments, R¹⁴ is 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino.

In some embodiments, there is the proviso that Formula (I) is not astructure selected from the group consisting of:

In some embodiments, R¹ is pyridineR³R⁴ or pyridin-3-ylR³R⁴.

In some embodiments, R¹ is pyridineR³R⁴.

In some embodiments, R¹ is pyridin-3-ylR³R⁴.

In some embodiments, R² is -heteroarylR⁵.

In some embodiments, R² is selected from -pyridinylR⁵, -pyridin-2-ylR⁵,-pyridin-3-ylR⁵, -pyridin-4-ylR⁵, thiopheneR⁵, furanR⁵, and imidazoleR⁵.

In some embodiments, R² is -pyridinylR⁵.

In some embodiments, R² is -pyridin-2-ylR⁵.

In some embodiments, R² is -pyridin-3-ylR⁵.

In some embodiments, R² is -pyridin-4-ylR⁵.

In some embodiments, R² is thiopheneR⁵.

In some embodiments, R² is furanR⁵.

In some embodiments, R² is imidazoleR⁵.

In some embodiments, R² is selected from the group consisting of

In some embodiments, R² is selected from -heterocyclylR⁶ and -arylR⁷.

In some embodiments, R² is selected from the group consisting ofmorpholine, piperazine, piperidine, and 1-methylpiperazine.

In some embodiments, R² is morpholine.

In some embodiments, R² is piperazine.

In some embodiments, R² is piperidine

In some embodiments, R² is 1-methylpiperazine.

In some embodiments, R² is -arylR⁷.

In some embodiments, R² is -phenylR⁷.

In some embodiments, R³ is selected from H, —(C₁₋₆ alkyl)NR¹¹R¹², —(C₁₋₄alkyl)NR¹¹R¹², —(C₁₋₂ alkyl)NR¹¹R¹², —CH₂NR¹¹R¹², —NR¹¹R¹², —NHC(═O)R⁹,—NHSO₂R¹⁰, and -heterocyclylR⁸.

In some embodiments, R³ is selected from H, —(C₁₋₆ alkyl)NR¹¹R¹², —(C₁₋₄alkyl)NR¹¹R¹², —(C₁₋₂ alkyl)NR¹¹R¹², —CH₂NR¹¹R¹², and —NR¹¹R¹².

In some embodiments, R³ is selected from morpholine, piperazine,piperidine, and 1-methylpiperazine.

In some embodiments, R³ is H.

In some embodiments, R³ is —(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R³ is —(C₁₋₄ alkyl)NR¹¹R¹².

In some embodiments, R³ is —(C₁₋₂ alkyl)NR¹¹R¹².

In some embodiments, R³ is —CH₂NR¹¹R¹².

In some embodiments, R³ is —NR¹¹R¹².

In some embodiments, R³ is —NHC(═O)R⁹.

In some embodiments, R³ is —NHSO₂R¹⁰.

In some embodiments, R³ is -heterocyclylR⁸.

In some embodiments, R³ is morpholine.

In some embodiments, R³ is piperazine.

In some embodiments, R³ is piperidine

In some embodiments, R³ is 1-methylpiperazine.

In some embodiments, R⁴ is H or amino.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is amino.

In some embodiments, R⁵ is 1-2 substituents selected from the groupconsisting of H, C₁₋₉ alkyl, halide, and —CF₃.

In some embodiments, R⁵ is 1-2 substituents selected from the groupconsisting of F, Cl, Br, and I.

In some embodiments, R⁵ is 1-2 fluorine atoms.

In some embodiments, R⁶ is selected from the group consisting of H, Fand —(C₁₋₄ alkyl).

In some embodiments, R⁶ is H.

In some embodiments, R⁶ is F.

In some embodiments, R⁶ is —(C₁₋₄ alkyl).

In some embodiments, R⁷ is selected from the group consisting of halide,—CF₃, —CN, —(C₁₋₆ alkyl)NHSO₂R¹¹, —(C₁₋₆ alkyl)NR¹¹R¹², and —NR¹²(C₁₋₆alkyl)NR¹¹R¹²;

In some embodiments, R⁷ is 1-2 fluorine atoms.

In some embodiments, R⁷ is —(C₁₋₆ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —(C₁₋₄ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —(C₁₋₂ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is —CH₂NHSO₂R¹¹.

In some embodiments, R⁷ is —CH₂NHSO₂CH₃.

In some embodiments, R⁷ is —NR¹²(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is —NR¹²(C₁₋₄ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is —NR¹²CH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is —NHCH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is —NHCH₂CH₂N(CH₃)₂.

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —NR¹²(C₁₋₆ alkyl)NR¹¹R¹².

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —NHCH₂CH₂NR¹¹R¹².

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —(C₁₋₆ alkyl)NHSO₂R¹¹.

In some embodiments, R⁷ is 2 substituents consisting of 1 fluorine atomand —CH₂NHSO₂R¹¹.

In some embodiments, R⁹ is selected from the group consisting of —(C₁₋₆alkyl), -aryl, -carbocyclyl, and —CH₂carbocyclyl;

In some embodiments, R⁹ is —(C₂₋₅ alkyl).

In some embodiments, R⁹ is —(C₁₋₆ alkyl).

In some embodiments, R⁹ is —(C₁₋₅ alkyl).

In some embodiments, R⁹ is —(C₁₋₄ alkyl).

In some embodiments, R⁹ is —(C₁₋₃ alkyl).

In some embodiments, R⁹ is —(C₁₋₂ alkyl).

In some embodiments, R⁹ is methyl.

In some embodiments, R⁹ is ethyl.

In some embodiments, R⁹ is propyl.

In some embodiments, R⁹ is isopropyl.

In some embodiments, R⁹ is n-butyl.

In some embodiments, R⁹ is isobutyl.

In some embodiments, R⁹ is tert-butyl.

In some embodiments, R⁹ is phenyl.

In some embodiments, R⁹ is —CH₂carbocyclyl.

In some embodiments, R⁹ is -carbocyclyl.

In some embodiments, R¹⁰ is selected from —(C₁₋₄ alkyl) and phenyl.

In some embodiments, R¹⁰ is —(C₁₋₄ alkyl).

In some embodiments, R¹⁰ is phenyl.

In some embodiments, R¹¹ is selected from the group consisting of —(C₁₋₂alkyl), —(C₁₋₃ alkyl), —(C₁₋₄ alkyl), —(C₁₋₅ alkyl), and —(C₁₋₆ alkyl).

In some embodiments, R¹¹ is —(C₁₋₂ alkyl).

In some embodiments, R¹¹ is —(C₁₋₃ alkyl).

In some embodiments, R¹¹ is —(C₁₋₄ alkyl).

In some embodiments, R¹¹ is —(C₁₋₅ alkyl).

In some embodiments, R¹¹ is —(C₁₋₆ alkyl).

In some embodiments, R¹¹ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In some embodiments, R¹¹ is methyl.

In some embodiments, R¹¹ is ethyl.

In some embodiments, R¹¹ is propyl.

In some embodiments, R¹¹ is isopropyl.

In some embodiments, R¹¹ is n-butyl.

In some embodiments, R¹¹ is isobutyl.

In some embodiments, R¹² is tert-butyl.

In some embodiments, R¹² is selected from the group consisting of H,—(C₁₋₂ alkyl), —(C₁₋₃ alkyl), —(C₁₋₄ alkyl), —(C₁₋₅ alkyl), and —(C₁₋₆alkyl).

In some embodiments, R¹² is H or —(C₁₋₂ alkyl).

In some embodiments, R¹² is H.

In some embodiments, R¹² is —(C₁₋₂ alkyl).

In some embodiments, R¹² is —(C₁₋₃ alkyl).

In some embodiments, R¹² is —(C₁₋₄ alkyl).

In some embodiments, R¹² is —(C₁₋₅ alkyl).

In some embodiments, R¹² is —(C₁₋₆ alkyl).

In some embodiments, R¹² is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

In some embodiments, R¹² is methyl.

In some embodiments, R¹² is ethyl.

In some embodiments, R¹² is propyl.

In some embodiments, R¹² is isopropyl.

In some embodiments, R¹² is n-butyl.

In some embodiments, R¹² is isobutyl.

In some embodiments, R¹² is tert-butyl.

In some embodiments, R¹¹ and R¹² are linked to form a five- orsix-membered heterocyclyl ring.

In some embodiments, R¹¹ and R¹² are linked to form a five- orsix-membered heterocyclyl ring selected from the group consisting of amorpholine ring, a piperidine ring, a pyrrolidine ring, a piperazinering, and

In some embodiments, R¹¹ and R¹² are linked to form a morpholine ring.

In some embodiments, R¹¹ and R¹² are linked to form a piperidine ring.

In some embodiments, R¹¹ and R¹² are linked to form a pyrrolidine ring.

In some embodiments, R¹¹ and R¹² are linked to form a piperazine ring.

In some embodiments, R¹¹ and R¹² are linked to form

In some embodiments, R¹ is -heteroarylR³R⁴; R² is -arylR⁷; R³ is—NHC(═O)R⁹; R⁴ is H; each R⁷ is independently 1-2 substituents eachselected from the group consisting of halide, —CF₃, —CN, —(C₁₋₆alkyl)NHSO₂R¹¹, —(C₁₋₆ alkyl)NR¹¹R¹² and —NR¹²(C₁₋₆ alkyl)NR¹¹R¹²; R⁹ isselected from the group consisting of —(C₁₋₆ alkyl), -aryl,-carbocyclyl, and —CH₂carbocyclyl; each R¹¹ is independently selectedfrom —(C₁₋₆ alkyl); each R¹² is independently selected from the groupconsisting of H and —(C₁₋₆ alkyl); and each R¹¹ and R¹² are optionallylinked to form a four- to six-membered heterocyclyl ring.

In some embodiments, R¹ is -pyridin-3-ylR³R⁴; R² is -phenylR⁷; R³ is a—NHC(═O)R⁹; R⁴ is H; each R⁷ is independently 1-2 substituents eachselected from the group consisting of fluorine, —CH₂NHSO₂R¹¹, —(C₁₋₆alkyl)NR¹¹R¹² and —NHCH₂CH₂NR¹¹R¹²; R⁹ is selected from the groupconsisting of —(C₂₋₅ alkyl), -phenyl, -carbocyclyl, and —CH₂carbocyclyl;each R¹¹ is independently selected from —(C₁₋₂ alkyl); each R¹² isindependently selected from the group consisting of H and —(C₁₋₂ alkyl);and each R¹¹ and R¹² are optionally linked to form a four- tosix-membered heterocyclyl ring.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is H; R⁴ is H; R² isselected from the group consisting of pyridine and -heterocyclylR⁶; andR⁶ is selected from the group consisting of H, F and —(C₁₋₄ alkyl).

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is H; R⁴ is amino; R² isselected from the group consisting of -heteroarylR⁵, -phenylR⁷ and-heterocyclylR⁶; R⁵ is H; R⁶ is selected from the group consisting of H,F and —(C₁₋₄ alkyl); R⁷ is 1-2 fluorine atoms; and the heteroaryl isselected from the group consisting of pyridine, furan and thiophene.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is —NHC(═O)R⁹; R⁴ is H;R⁹ is selected from the group consisting of ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and phenyl; R² is selected from the groupconsisting of H, -heteroarylR⁵, -phenylR⁷ and -heterocyclylR⁶;

R⁵ is H or F; R⁶ is selected from the group consisting of H, F and—(C₁₋₄ alkyl); R⁷ is selected from the group consisting of 1-2 fluorineatoms and —CH₂NHSO₂R¹¹; and the heteroaryl is selected from the groupconsisting of pyridine, furan and thiophene.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is —CH₂NR¹¹R¹²; R⁴ is H;R² is selected from the group consisting of H, -heteroarylR⁵, -phenylR⁷and -heterocyclylR⁶; R⁵ is selected from the group consisting of H, F,Me and —C(═O)Me; R⁶ is selected from the group consisting of H, F and—(C₁₋₄ alkyl); R⁷ is 1-2 fluorine atoms; R¹¹ and R¹² are linked to forma five-membered heterocyclyl ring; the heterocyclyl ring is substitutedwith 1-2 fluorine atoms; and the heteroaryl is selected from the groupconsisting of pyridine, furan and thiophene.

In some embodiments, R¹ is pyridin-3-ylR³R⁴; R³ is —NHC(═O)R⁹; R⁴ is H;R⁹ is —(C₁₋₄ alkyl); R² is -arylR⁷; and R⁷ is F.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

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In some embodiments, the compound of Formula (I) has a structureselected from:

In some embodiments, the compound of Formula (I) has a structureselected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has the structure

or a polymorph or pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula (I) is Compound 10, or a polymorphthereof.

3. Polymorphs

Provided herein is a compound of Formula (I), Compound 10:

including amorphous and polymorph forms thereof.

Compound 10 provided herein can be prepared using methods known andunderstood by those of ordinary skill in the art. For example, syntheticmethods such as those described in US 2013/0267495 can be used, and thisapplication is herein incorporated by reference in its entirety.

Also provided herein are polymorph forms of the compound of Compound 10.The forms include, e.g., solvates, hydrates, non-stoichiometrichydrates, and non-solvated forms of Compound 10, including, for example,polymorph Forms 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13.

One such polymorph is a polymorph known as Form 1. Form 1 is ananhydrous polymorph of the compound of Compound 10. In one embodiment,Form 1 has an X-ray powder diffraction (XRPD or XRD) pattern, obtainedwith CuKα1-radiation, with at least peaks at °2θ values of 6.8±0.2,12.4±0.2, and 18.5±0.2. In some embodiments, Form 1 has an XRPD patternwith at least peaks at °2θ values of 6.8±0.2, 12.4±0.2, 16.5±0.2,18.5±0.2, and 19.2±0.2. In some embodiments, Form 1 has an XRPD patternwith at least peaks at °2θ values of 6.8±0.2, 9.3±0.2, 12.4±0.2,13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2. For example, insome embodiments, Form 1 has an XRPD pattern with at least peaks at °2θvalues of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 14.5±0.2, 16.5±0.2,18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 1. In some embodiments, the composition can besubstantially pure. For example, the composition has a purity of atleast about 90%. In some embodiments, the composition has a purity of atleast about 95%. In some embodiments, the composition has a purity of atleast about 98%. For example, the composition can have a purity of atleast 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%,99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, thecomposition is substantially free of other forms of Compound 10. Forexample, in some embodiments, the composition is substantially free ofother anhydrous forms of Compound 10. In some embodiments, thecomposition contains less than about 15% by weight of other forms of thecompound of Compound 10. For example, the composition can contain lessthan 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lessby weight of other anhydrous forms of the compound of Compound 10. Insome embodiments, the composition contains less than about 15% by weightof the polymorph Form 9. For example, the composition can contain lessthan 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lessby weight of the polymorph of Form 9. In some embodiments, thecomposition contains less than about 15% by weight of one or more otherforms of Compound 10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weight of one or more other formsof Compound 10. For example, the composition can contain less than about15% of Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9,Form 10, Form 11, a non-stoichiometric hydrate of Form 1 having between1% and about 20% by weight water, or a combination of two or morethereof.

In some embodiments, provided herein is polymorph Form 1 that exhibitsan endotherm between about 50-100° C. as measured by differentialscanning calorimetry (DSC) related to sorbed water. In some embodiments,polymorph Form 1 exhibits a recrystallization event that is observedbetween about 270-290° C., e.g., around 280° C. In some embodiments, theendotherm and exotherm are observed when using a scan rate of 10° C. perminute.

In some embodiments, provided herein is polymorph Form 1 thatrecrystallizes into Form 9 with a melting point of around 363° C. Insome embodiments, polymorph Form 1 undergoes a total mass loss of about0.33% before around 100° C., e.g., from about 39° C. to about 100° C.,as measured by thermal gravimetric analysis (TGA).

Provided herein are methods of preparing polymorph Form 1. In someembodiments, the method comprises drying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, togenerate polymorph Form 1. In some embodiments, the compositioncomprises a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water. In some embodiments, the method comprisesreslurrying a composition comprising Compound 10, including amorphousand polymorph forms thereof, in a solvent or mixture of solvents togenerate polymorph Form 1 as a residual solid. In some embodiments, thereslurrying takes place at room temperature (RT). In some embodiments,the reslurrying takes place at around 50° C. In some embodiments, themethod further comprises drying the residual solid, for example, undervacuum. In some embodiments, the drying is at a temperature of betweenabout 60° C. and 90° C., such as, e.g., around 75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising Compound 10, including amorphous and polymorph forms thereofin a solvent or mixture of solvents to generate polymorph Form 1 as aresidual solid. In some embodiments, Compound 10 is a non-stoichiometrichydrate of Form 1 having between 1% and about 20% by weight water. Insome embodiments, the solvent is methanol. In some embodiments, thesolvent is toluene. In some embodiments, the solvent is heptane. In someembodiments, the solvent is dichloromethane (DCM). In some embodiments,the solvent is water. In some embodiments, the solvent is in a mixturewith water, for example the solvent can be a mixture of water andacetonitrile, methanol, ethyl acetate (EA), methyl tert-butyl ether(MtBE), isopropyl alcohol (IPAc), methyl acetate (MA), methyl isobutylketone (MIBK), DCM, n-butyl acetate, heptane, toluene, or n-butanol. Insome embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at roomtemperature. In some embodiments, the reslurrying takes place at around50° C. In some embodiments, the method further comprises drying theresidual solid, for example, under vacuum. In some embodiments, thedrying is at a temperature of between about 60° C. and 90° C., such as,e.g., around 75° C.

Provided herein is a non-stoichiometric hydrate of Form 1 having between1% and about 20% by weight water. In some embodiments, for example,above 30% relative humidity (RH), Form 1 readily sorbs water and shows adistinctive shift in Form 1 peaks from 6.8±0.2 to 6.2±0.2 and 12.6±0.2to 11±0.2. In some embodiments, a non-stoichiometric hydrate of Form 1comprises up to about 20% by weight water. For example, up to about 20%,about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%,about 6%, about 5%, about 4%, about 3%, about 2%, or greater than 1%water by weight. In some embodiments, a non-stoichiometric hydrate ofForm 1 has between 1 to about 20% water by weight, e.g., between 1% andabout 10%, about 5% and about 15%, about 10% and about 20%, 1% and about5%, about 5% and about 10%, about 10% and about 15%, about 15% and about20%, or about 17% and about 20% water by weight.

In some embodiments, provided herein is a composition comprising anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of anhydrous forms ofCompound 10. In some embodiments, the composition contains less than 15%by weight of other forms of Compound 10, such as less than 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weight ofother forms of Compound 10 (e.g., anhydrous forms of Compound 10). Insome embodiments, the composition contains less than 20% by weight ofpolymorph Form 9 having X-ray powder diffraction pattern comprisingpeaks at °2θ values of 4.9±0.2, 18.6±0.2, and 21.1±0.2. For example, thecomposition contains less than 15% by weight of Form 9, such as lessthan 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lessby weight of other forms of the compound of Form 9. In some embodiments,the composition contains less than 15% of one or more other forms ofCompound 10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1% or less of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10,Form 11, or a combination of two or more thereof.

Another example of a non-stoichiometric hydrate of polymorph Form 1 isreferred to as Form 12. Form 12 is a non-stoichiometric hydrate ofpolymorph Form 1 that has 1.42% water by weight.

In one embodiment, provided herein is a polymorph Form 12 having an XRPDpattern, obtained with CuKα1-radiation, with at least peaks at °2θpositions 6.4±0.2, 11.0±0.2, and 18.4±0.2. In some embodiments, Form 12has an XRPD pattern with at least peaks at °2θ positions 6.4±0.2,9.2±0.2, 11.0±0.2, 18.4±0.2, and 19.7±0.2. In some embodiments, Form 12has an XRPD pattern with at least peaks at °2θ positions 6.4±0.2,9.2±0.2, 11.0±0.2, 15.6±0.2, 18.4±0.2, 19.7±0.2, 24.4±0.2, and 25.2±0.2.For example, in some embodiments, Form 12 has an XRPD pattern with atleast peaks at °2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2, 15.6±0.2,16.1±0.2, 18.4±0.2, 19.7±0.2, 20.8±0.2, 24.4±0.2, and 25.2±0.2.

In some embodiments, provided herein is polymorph Form 12 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 12 exhibits an exotherm at around 283° C. Insome embodiments, the endotherms and exotherms are observed when using ascan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 12 that has amelting point of around 364° C. In some embodiments, polymorph Form 12undergoes a weight loss of about 1.4% before around 100° C., e.g., fromabout 30° C. to about 100° C., as measured by TGA.

One example of a non-stoichiometric hydrate of polymorph Form 1 isreferred to as Form 13. Form 13 is a non-stoichiometric hydrate ofpolymorph Form 1 that has 1.84% water by weight.

In one embodiment, provided herein is polymorph Form 13 having an XRPDpattern, obtained with CuKα1-radiation, with at least peaks at °2θvalues of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, Form 13has an XRPD pattern with at least peaks at °2θ values of 6.8±0.2,12.4±0.2, 16.5±0.2, 18.5±0.2, and 19.2±0.2. In some embodiments, Form 13has an XRPD pattern with at least peaks at °2θ values of 6.8±0.2,9.3±0.2, 12.4±0.2, 13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2.For example, in some embodiments, Form 13 has an XRPD pattern with atleast peaks at °2θ values of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2,14.5±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

In some embodiments, provided herein is polymorph Form 13 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 13 exhibits an exotherm at between about265-285° C., e.g., around 278° C. For example, in some embodiments, theendotherms and exotherms are observed when using a scan rate of 10° C.per minute.

In some embodiments, provided herein is polymorph Form 13 that has amelting point of around 363° C. In some embodiments, polymorph Form 13undergoes a weight loss of about 1.9% before around 100° C. as measuredby TGA.

Provided herein are methods of preparing a non-stoichiometric hydrate ofpolymorph Form 1. In some embodiments, the method comprises reslurryinga composition comprising Compound 10, including amorphous and polymorphforms thereof, in a solvent or mixture of solvents to generate anon-stoichiometric hydrate of polymorph Form 1 as a residual solid. Insome embodiments, the composition comprising Compound 10 is a mixture ofa non-stoichiometric hydrate of polymorph Form 1 and Form 1. In someembodiments, the reslurrying takes place at RT. In some embodiments, thereslurrying takes place at around 50° C. In some embodiments, the methodfurther comprises drying the residual solid, for example, under vacuum.In some embodiments, the drying is at a temperature of between about 60°C. and 90° C., such as, e.g., around 75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a mixture of a non-stoichiometric hydrate of polymorph Form 1and Form 1 in a solvent or mixture of solvents to generate anon-stoichiometric hydrate of polymorph Form 1 as a residual solid. Insome embodiments, the solvent is in a mixture with water, for examplethe solvent can be a mixture of water and acetonitrile, methanol, MtBE,MA, MIBK, DCM, IPAc, n-butyl acetate, heptane, toluene, or n-butanol. Insome embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 2. Form 2 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 2 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 7.0±0.2, 21.5±0.2, and 22.0±0.2. Insome embodiments, Form 2 has an XRPD pattern with at least peaks at °2θvalues of 7.0±0.2, 18.9±0.2, 21.5±0.2, 22.0±0.2, and 24.2±0.2. In someembodiments, Form 2 has an XRPD pattern with at least peaks at °2θvalues of 7.0±0.2, 14.1±0.2, 18.9±0.2, 19.2±0.2, 21.5±0.2, 22.0±0.2,24.2±0.2, and 26.4±0.2. For example, in some embodiments, Form 2 has anXRPD pattern with at least peaks at °2θ values of 7.0±0.2, 10.4±0.2,14.1±0.2, 17.6±0.2, 18.9±0.2, 19.2±0.2, 21.5±0.2, 22.0±0.2, 24.2±0.2,and 26.4±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 2. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 2 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 2 exhibits an endotherm between about220-230° C. In some embodiments, polymorph Form 2 exhibits an exothermbetween about 233-238° C. In some embodiments, polymorph Form 2 exhibitsan exotherm between about 290-295° C. In some embodiments, theendotherms and exotherms are observed when using a scan rate of 10° C.per minute.

In some embodiments, provided herein is polymorph Form 2 that has amelting point of around 363° C. In some embodiments, polymorph Form 2undergoes a weight loss of about 2.7% before around 116° C., e.g., fromabout 36° C. to about 116° C., as measured by TGA.

Provided herein are methods of preparing polymorph Form 2. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 2 as a residual solid.In some embodiments, the composition comprising Compound 10 comprises anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 2 as a residual solid. In some embodiments, thesolvent is acetonitrile. In some embodiments, the solvent is ethanol. Insome embodiments, the solvent is in a mixture with water, for examplethe solvent can be a mixture of water and ethanol or water andn-propanol. In some embodiments, the water is present in an amount ofabout 5% by weight. In some embodiments, the reslurrying takes place atRT. In some embodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 3. Form 3 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 3 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 7.2±0.2, 22.2±0.2, and 24.4±0.2. Insome embodiments, Form 3 has an XRPD pattern with at least peaks at °2θvalues of 6.3±0.2, 7.2±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2. In someembodiments, Form 3 has an XRPD pattern with at least peaks at °2θvalues of 6.3±0.2, 7.2±0.2, 11.0±0.2, 18.4±0.2, 19.0±0.2, 21.6±0.2,22.2±0.2, and 24.4±0.2. For example, in some embodiments, Form 3 has anXRPD pattern with at least peaks at °2θ values of 6.3±0.2, 7.2±0.2,11.0±0.2, 14.2±0.2, 17.8±0.2, 18.4±0.2, 19.0±0.2, 21.6±0.2, 22.2±0.2,and 24.4±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 3. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 3 that exhibitsan exotherm between about 190-220° C., as measured by DSC. In someembodiments, polymorph Form 3 exhibits an exotherm at between about225-235° C., e.g., around 230° C., as measured by DSC. In someembodiments, polymorph Form 3 exhibits an exotherm at between about292-300° C., e.g., around 297° C., as measured by DSC. For example, insome embodiments, the endotherms and exotherms are observed when using ascan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 3 that has amelting point of around 365° C. In some embodiments, polymorph Form 3undergoes a weight loss of about 1.6% before around 81° C. and a weightloss of about 1.7% between about 81-169° C. as measured by TGA.

Provided herein are methods of preparing polymorph Form 3. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 3 as a residual solid.In some embodiments, the composition comprising Compound 10 comprises anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 3 as a residual solid. In some embodiments, thesolvent is IPAc. In some embodiments, the solvent is n-butyl acetate. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 4. Form 4 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 4 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 7.0±0.2, 21.8±0.2, and 25.1±0.2. Insome embodiments, Form 4 has an XRPD pattern with at least peaks at °2θvalues of 7.0±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2, and 25.1±0.2. In someembodiments, Form 4 has an XRPD pattern with at least peaks at °2θvalues of 7.0±0.2, 17.6±0.2, 18.3±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2,25.1±0.2, and 25.8±0.2. For example, in some embodiments, Form 4 has anXRPD pattern with at least peaks at °2θ values of 7.0±0.2, 9.6±0.2,17.6±0.2, 18.3±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2, 25.1±0.2, 25.8±0.2,and 29.3±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 4. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 4 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 4 exhibits an endotherm at between about180-215° C. In some embodiments, polymorph Form 4 exhibits an endothermbetween about 220-230° C. In some embodiments, polymorph Form 4 exhibitsan exotherm at between about 230-240° C., e.g., around 235° C. In someembodiments, polymorph Form 4 exhibits an exotherm at between about300-310° C. For example, in some embodiments, the endotherms andexotherms are observed when using a scan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 4 that has amelting point of between about 366-369° C., e.g., around 367° C. In someembodiments, polymorph Form 4 undergoes a weight loss of about 8.3%before around 200° C., e.g., from about 42° C. to about 200° C., asmeasured by TGA.

Provided herein are methods of preparing polymorph Form 4. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 4 as a residual solid.In some embodiments, the composition comprising Compound 10 comprises anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 4 as a residual solid. In some embodiments, thesolvent is EA. In some embodiments, the solvent is MA. In someembodiments, the solvent is MtBE. In some embodiments, the solvent isn-propanol. In some embodiments, the solvent is acetone. In someembodiments, the solvent is in a mixture with water, for example thesolvent can be a mixture of water and MA, EA, or acetone. In someembodiments, the water is present in an amount of about 5% by weight. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 5. Form 5 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 5 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 7.3±0.2, 22.3±0.2, and 24.5±0.2. Insome embodiments, Form 5 has an XRPD pattern with at least peaks at °2θvalues of 6.3±0.2, 7.3±0.2, 21.7±0.2, 22.3±0.2, and 24.5±0.2. In someembodiments, Form 5 has an XRPD pattern with at least peaks at °2θvalues of 6.3±0.2, 7.3±0.2, 11.0±0.2, 19.1±0.2, 19.5±0.2, 21.7±0.2,22.3±0.2, and 24.5±0.2. For example, in some embodiments, Form 5 has anXRPD pattern with at least peaks at °2θ values of 6.3±0.2, 7.3±0.2,11.0±0.2, 14.3±0.2, 19.1±0.2, 19.5±0.2, 21.7±0.2, 22.3±0.2, 24.5±0.2,and 26.5±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 5. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 6, Form 7, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 5 that exhibitsan endotherm between about 50-100° C. as measured by DSC. In someembodiments, polymorph Form 5 exhibits an endotherm at between about210-235° C., e.g., around 222° C. In some embodiments, polymorph Form 5exhibits an exotherm at between about 227-240° C., e.g., around 235° C.In some embodiments, polymorph Form 5 exhibits an exotherm at betweenabout 280-300° C., e.g., around 293° C. For example, in someembodiments, the endotherms and exotherms are observed when using a scanrate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 5 that has amelting point of around 363° C. In some embodiments, polymorph Form 5undergoes a weight loss of about 3.1% before around 100° C. and about1.7% between about 100-250° C. as measured by TGA.

Provided herein are methods of preparing polymorph Form 5. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 5 as a residual solid.In some embodiments, the composition comprising Compound 10 comprises anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 5 as a residual solid. In some embodiments, thesolvent is MtBE. In some embodiments, the reslurrying takes place at RT.In some embodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 6. Form 6 is an anhydrouspolymorph of Compound 10.

In some embodiments, provided herein is a composition comprisingpolymorph Form 6. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 7, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 6 that exhibitsan exotherm between about 245-260° C. as measured by DSC. For example,in some embodiments, the endotherms and exotherms are observed whenusing a scan rate of 10° C. per minute. In some embodiments, providedherein is polymorph Form 6 that has a melting point of around 364° C.

Provided herein are methods of preparing polymorph Form 6. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 6 as a residual solid.In some embodiments, the composition comprising Compound 10 is anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 6 as a residual solid. In some embodiments, thesolvent is IPAc. In some embodiments, the solvent is in a mixture withwater, for example the solvent can be a mixture of water and IPAc. Insome embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 7. Form 7 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 7 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 7.1±0.2, 21.6±0.2, and 23.2±0.2. Insome embodiments, Form 7 has an XRPD pattern with at least peaks at °2θvalues of 4.9±0.2, 7.1±0.2, 18.5±0.2, 21.6±0.2, and 23.2±0.2. In someembodiments, Form 7 has an XRPD pattern with at least peaks at °2θvalues of 4.9±0.2, 7.1±0.2, 10.9±0.2, 18.5±0.2, 19.4±0.2, 21.6±0.2,23.2±0.2, and 30.3±0.2. For example, in some embodiments, Form 7 has anXRPD pattern with at least peaks at °2θ values of 4.9±0.2, 7.1±0.2,8.8±0.2, 10.9±0.2, 18.5±0.2, 19.4±0.2, 21.6±0.2, 22.1±0.2, 23.2±0.2, and30.3±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 7. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 8, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 7 that exhibitsan exotherm between about 227-235° C., e.g., around 232° C., as measuredby DSC. In some embodiments, polymorph Form 7 exhibits an exothermbetween about 299-305° C., e.g., around 303° C. For example, in someembodiments, the endotherms and exotherms are observed when using a scanrate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 7 that has amelting point of around 365° C. In some embodiments, polymorph Form 7undergoes a weight loss of about 12% before around 200° C., e.g., fromabout 36° C. to about 200° C., as measured by TGA.

Provided herein are methods of preparing polymorph Form 7. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 7 as a residual solid.In some embodiments, the composition comprising Compound 10 is anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 7 as a residual solid. In some embodiments, thesolvent is methyl ethyl ketone (MEK). In some embodiments, the solventis in a mixture with water, for example the solvent can be a mixture ofwater and MEK. In some embodiments, the water is present in an amount ofabout 5% by weight. In some embodiments, the reslurrying takes place atRT. In some embodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 8. Form 8 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 8 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 6.9±0.2, 17.7±0.2, and 21.5±0.2. Insome embodiments, Form 8 has an XRPD pattern with at least peaks at °2θvalues of 6.9±0.2, 11.5±0.2, 17.7±0.2, 21.5±0.2, and 27.6±0.2. In someembodiments, Form 8 has an XRPD pattern with at least peaks at °2θvalues of 6.9±0.2, 11.5±0.2, 15.3±0.2, 16.9±0.2, 17.7±0.2, 21.5±0.2,27.6±0.2, and 28.9±0.2. For example, in some embodiments, Form 8 has anXRPD pattern with at least peaks at °2θ values of 6.9±0.2, 11.5±0.2,12.7±0.2, 14.2±0.2, 15.3±0.2, 16.9±0.2, 17.7±0.2, 21.5±0.2, 27.6±0.2,and 28.9±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 8. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 9, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 8 that exhibitsan endotherm between about 41-60° C. as measured by DSC. In someembodiments, polymorph Form 8 exhibits an exotherm at between about221-235° C., e.g., around 231° C. In some embodiments, polymorph Form 8exhibits an endotherm between about 279-290° C., e.g., around 285° C.For example, in some embodiments, the endotherms and exotherms areobserved when using a scan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 8 that has amelting point of around 364° C. In some embodiments, polymorph Form 8undergoes a weight loss of about 4.2% before around 190° C. and about3.9% between about 190-261° C. as measured by TGA.

Provided herein are methods of preparing polymorph Form 8. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 8 as a residual solid.In some embodiments, the composition comprising Compound 10 anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 8 as a residual solid. In some embodiments, thesolvent is MIBK. In some embodiments, the reslurrying takes place at RT.In some embodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 9. Form 9 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 9 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 4.9±0.2, 18.6±0.2, and 21.1±0.2. Insome embodiments, Form 9 has an XRPD pattern with at least peaks at °2θvalues of 4.9±0.2, 18.6±0.2, 21.1±0.2, 24.1±0.2, and 25.2±0.2. In someembodiments, Form 9 has an XRPD pattern with at least peaks at °2θvalues of 4.9±0.2, 15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2, 22.4±0.2,24.1±0.2, and 25.2±0.2. For example, in some embodiments, Form 9 has anXRPD pattern with at least peaks at °2θ values of 4.9±0.2, 10.1±0.2,15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2, 22.4±0.2, 24.1±0.2, 25.2±0.2,and 28.6±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 9. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 10, Form11, a non-stoichiometric hydrate of Form 1, or a combination of two ormore thereof.

In some embodiments, provided herein is polymorph Form 9 that exhibits asingle melting endotherm at around 364° C. as measured by DSC. Forexample, in some embodiments, the endotherm is observed when using ascan rate of 10° C. per minute. In some embodiments, other polymorphforms provided herein, such as, e.g., Form 1 and Form 2, can convert toForm 9 when heated to just before melting (i.e., around 364° C.).

In some embodiments, provided herein is polymorph Form 9 that has amelting point of around 364° C. In some embodiments, polymorph Form 9undergoes a weight loss of about 0.28% before around 100° C., e.g., fromabout 30.5° C. to about 100° C., as measured by TGA.

Provided herein are methods of preparing polymorph Form 9. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 9 as a residual solid.In some embodiments, the composition comprising Compound 10 is anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 9 as a residual solid. In some embodiments, thesolvent is n-butanol. In some embodiments, the solvent is IPAc. In someembodiments, the solvent is n-butyl acetate. In some embodiments, thesolvent is in a mixture with water, for example the solvent can be amixture of water and ethanol or water and n-propanol. In someembodiments, the water is present in an amount of about 5% by weight. Insome embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 10. Polymorph Form 10 is apolymorph of Compound 10 comprising DMSO. For example, DMSO is on thesurface of the polymorph. In one embodiment, provided herein ispolymorph Form 10 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 20.7±0.2, 21.7±0.2, and 24.2±0.2.In some embodiments, Form 10 has an XRPD pattern with at least peaks at°2θ values of 18.2±0.2, 19.0±0.2, 20.7±0.2, 21.7±0.2, and 24.2±0.2. Insome embodiments, Form 10 has an XRPD pattern with at least peaks at °2θvalues of 17.8±0.2, 18.2±0.2, 19.0±0.2, 20.7±0.2, 21.7±0.2, 23.4±0.2,24.2±0.2, and 27.9±0.2. For example, in some embodiments, Form 10 has anXRPD pattern with at least peaks at °2θ values of 6.7±0.2, 17.8±0.2,18.2±0.2, 19.0±0.2, 19.9±0.2, 20.7±0.2, 21.7±0.2, 23.4±0.2, 24.2±0.2,and 27.9±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 10. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 11,a non-stoichiometric hydrate of Form 1, or a combination of two or morethereof.

In some embodiments, provided herein is polymorph Form 10 that exhibitsan endotherm between about 212-237° C. as measured by DSC. In someembodiments, polymorph Form 10 exhibits an endotherm at between about234-245° C., e.g., around 237° C. In some embodiments, polymorph Form 10exhibits an exotherm between about 300-325° C., e.g., around 308° C. Forexample, in some embodiments, the endotherms and exotherms are observedwhen using a scan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 10 that has amelting point of between about 364-372° C., such as, e.g., around 369°C. In some embodiments, polymorph Form 10 undergoes a weight loss ofabout 0.6% before around 100° C., a weight loss of about 3.8% betweenabout 100-170° C., and a weight loss of about 7.1% between about170-260° C. as measured by TGA.

Provided herein are methods of preparing polymorph Form 10. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 10 as a residual solid.In some embodiments, the composition comprising Compound 10 is anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 10 as a residual solid. In some embodiments, thesolvent is DMSO. In some embodiments, the solvent is in a mixture withwater, for example the solvent can be a mixture of water and DMSO. Insome embodiments, the water is present in an amount of about 5% byweight. In some embodiments, the reslurrying takes place at RT. In someembodiments, the reslurrying takes place at around 50° C.

Provided herein is a polymorph known as Form 11. Form 11 is an anhydrouspolymorph of Compound 10. In one embodiment, provided herein ispolymorph Form 11 having an XRPD pattern, obtained with CuKα1-radiation,with at least peaks at °2θ values of 6.4±0.2, 18.5±0.2, and 22.4±0.2. Insome embodiments, Form 11 has an XRPD pattern with at least peaks at °2θvalues of 6.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, and 22.4±0.2. In someembodiments, Form 11 has an XRPD pattern with at least peaks at °2θvalues of 6.4±0.2, 8.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, 22.4±0.2,24.5±0.2, and 26.8±0.2. For example, in some embodiments, Form 11 has anXRPD pattern with at least peaks at °2θ values of 6.4±0.2, 8.4±0.2,17.8±0.2, 18.5±0.2, 19.9±0.2, 20.3±0.2, 22.4±0.2, 22.9±0.2, 24.5±0.2,and 26.8±0.2.

In some embodiments, provided herein is a composition comprisingpolymorph Form 11. In some embodiments, the composition is substantiallypure. For example, the composition can have a purity of at least about90%. In some embodiments, the composition has a purity of at least about95%. In some embodiments, the composition has a purity of at least about98%. For example, the composition can have a purity of at least 98.5%,98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%,99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition issubstantially free of other forms of Compound 10. For example, in someembodiments, the composition is substantially free of other anhydrousforms of Compound 10. In some embodiments, the composition contains lessthan 15% by weight of other forms of Compound 10, such as less than 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less by weightof other forms of Compound 10. In some embodiments, the compositioncontains less than 15% by weight of one or more other forms of Compound10, such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1% or less by weight of one or more other forms of Compound 10.For example, the composition can contain less than about 15% of Form 1,Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10,a non-stoichiometric hydrate of Form 1, or a combination of two or morethereof.

In some embodiments, provided herein is polymorph Form 11 that exhibitsan endotherm between about 215-230° C. as measured by DSC. In someembodiments, polymorph Form 11 exhibits an exotherm at between about230-240° C., e.g., around 235° C. In some embodiments, polymorph Form 11exhibits an exotherm between about 300-315° C., e.g., around 310° C. Forexample, in some embodiments, the endotherms and exotherms are observedwhen using a scan rate of 10° C. per minute.

In some embodiments, provided herein is polymorph Form 11 that has amelting point of around 368° C. In some embodiments, polymorph Form 11undergoes a weight loss of about 0.8% before around 100° C. and a weightloss of about 7.0% between about 100-249° C., as measured by TGA.

Provided herein are methods of preparing polymorph Form 11. In someembodiments, the method comprises reslurrying a composition comprisingCompound 10, including amorphous and polymorph forms thereof, in asolvent or mixture of solvents to generate Form 11 as a residual solid.In some embodiments, the composition comprising Compound 10 is anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. In some embodiments, the reslurrying takes place at RT. Insome embodiments, the slurrying takes place at around 50° C. In someembodiments, the method further comprises drying the residual solid, forexample, under vacuum. In some embodiments, the drying is at atemperature of between about 60° C. and 90° C., such as, e.g., around75° C.

In some embodiments, the method comprises reslurrying a compositioncomprising a non-stoichiometric hydrate of Form 1 having between 1% andabout 20% by weight water in a solvent or mixture of solvents togenerate polymorph Form 11 as a residual solid. In some embodiments, thesolvent is dimethylformamide (DMF). In some embodiments, the solvent isin a mixture with water, for example the solvent can be a mixture ofwater and DMF. In some embodiments, the water is present in an amount ofabout 5% by weight. In some embodiments, the reslurrying takes place atRT. In some embodiments, the reslurrying takes place at around 50° C.

4. Pharmaceutical Compositions and Administration

Provided are pharmaceutical compositions for use in the methodsdescribed herein comprising a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier. In some embodiments, thecompound of Formula (I) is Compound 10. In some embodiments, thecompound of Formula (I) is a polymorph form of Compound 10.

In some embodiments, the compounds of Formula (I), includingpharmaceutically acceptable salts thereof, are formulated in combinationwith a conventional pharmaceutical carrier, excipient or the like.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS), such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage formssuch as Tweens, poloxamers or other similar polymeric delivery matrices,serum proteins, such as human serum albumin, buffer substances, such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriercan be prepared. Actual methods of preparing such dosage forms areknown, or will be apparent, to those skilled in this art; for example,see Remington: The Science and Practice of Pharmacy, 22^(nd) Edition(Pharmaceutical Press, London, UK. 2012).

The contemplated compositions can contain 0.001%-100% of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, e.g., in oneembodiment 0.1-95%, in another embodiment 75-85%, and in a furtherembodiment 20-80%. In some embodiments, the pharmaceutical compositioncan comprise between about 0.1% and 10% of a compound of Formula (I), ora pharmaceutically acceptable salt thereof. For example, the compositioncan comprise between about 0.1-10%, 0.1-5%, 0.1-4%, 0.15-3%, or 0.2-2%of a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In some embodiments, the composition comprises about 0.001 mg to about5.0 mg per dose of a compound of Formula (I), including pharmaceuticallyacceptable salts thereof. For example, the composition in someembodiments comprises about 0.001 mg to about 4 mg, about 0.001 mg toabout 3 mg, about 0.001 mg to about 2 mg, about 0.001 mg to about 1 mg,about 0.001 mg to about 0.5 mg, 0.001 mg to about 0.4 mg, about 0.001 mgto about 0.3 mg, about 0.001 mg to about 0.25 mg, about 0.001 mg toabout 0.2 mg, about 0.001 mg to about 0.15 mg, about 0.001 mg to about0.1 mg, about 0.001 mg to about 0.075 mg, about 0.001 mg to about 0.055mg, about 0.001 mg to about 0.05 mg, about 0.001 mg to about 0.035 mg,about 0.001 mg to about 0.025 mg, about 0.001 mg to about 0.01 mg, about0.001 mg to about 0.005 mg, about 0.005 mg to about 5.0 mg, about 0.0075mg to about 5.0 mg, about 0.01 mg to about 5.0 mg, about 0.01 mg toabout 4.0 mg, about 0.01 mg to about 3.0 mg, about 0.01 mg to about 2.0mg, about 0.01 mg to about 1.0 mg, about 0.01 mg to about 0.7 mg, about0.01 mg to about 0.5 mg, about 0.01 mg to about 0.3 mg, about 0.01 mg toabout 0.23 mg, about 0.01 mg to about 0.1 mg, about 0.01 mg to about0.07 mg, about 0.01 mg to about 0.05 mg, about 0.01 mg to about 0.03 mg,about 0.03 mg to about 4.0 mg, about 0.03 mg to about 3.0 mg, about 0.03mg to about 2.0 mg, about 0.03 mg to about 1.0 mg, about 0.03 mg toabout 0.7 mg, about 0.03 mg to about 0.5 mg, about 0.03 mg to about 0.3mg, about 0.03 mg to about 0.23 mg, about 0.03 mg to about 0.1 mg, about0.03 mg to about 0.07 mg, about 0.03 mg to about 0.05 mg, about 0.07 mgto about 4.0 mg, about 0.07 mg to about 3.0 mg, about 0.07 mg to about2.0 mg, about 0.07 mg to about 1.0 mg, about 0.07 mg to about 0.7 mg,about 0.07 mg to about 0.5 mg, about 0.07 mg to about 0.3 mg, about 0.07mg to about 0.23 mg, about 0.07 mg to about 0.1 mg, about 0.025 mg toabout 5.0 mg, about 0.045 mg to about 5.0 mg, about 0.05 mg to about 5.0mg, about 0.075 mg to about 5.0 mg, about 0.1 mg to about 5.0 mg, about0.25 mg to about 5.0 mg, about 0.01 mg to about 3.0 mg, about 0.025 mgto about 2.0 mg, about 0.01 mg to about 0.1 mg, and about 0.15 mg toabout 0.25 mg of the compound of Formula (I), including amorphous andpolymorph forms thereof. In some embodiments, the composition comprisesabout 0.001 mg, 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.07 mg, 0.1 mg,0.23 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.2 mg, 1.5 mg, 1.7 mg, 2.0mg, 2.2 mg, 2.5 mg, 2.7 mg, 3.0 mg, 3.2 mg, 3.5 mg, 3.7 mg, 4.0 mg, 4.2mg, 4.5 mg, 4.7 mg, or 5.0 mg of the compound of Formula (I), includingamorphous and polymorph forms thereof. In some embodiments, the compoundof Formula (I) is Compound 10. In some embodiments, the compound ofFormula (I) is a polymorph form of Compound 10. In some embodiments, thepolymorph form of Compound 10 is dried prior to mixing with thepharmaceutically acceptable carrier.

The compounds provided herein, e.g., compounds of Formula (I), includingpharmaceutically acceptable salts thereof, intended for pharmaceuticaluse can be administered as crystalline or amorphous products.Pharmaceutically acceptable compositions include solid, semi-solid,liquid, solution, colloidal, liposome, emulsion, suspension, complex,coacervate and aerosol compositions. Dosage forms include, e.g.,tablets, capsules, powders, liquids, suspensions, suppositories,aerosols, implants, controlled release or the like. They can beobtained, for example, as solid plugs, powders, or films by methods suchas precipitation, crystallization, milling, grinding, supercriticalfluid processing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying can be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

In one embodiment, the composition takes the form of a unit dosage formsuch as a pill or tablet and thus the composition can contain, alongwith a compound of Formula (I), or a pharmaceutically acceptable saltthereof, a diluent such as lactose, sucrose, dicalcium phosphate, or thelike; a lubricant such as magnesium stearate or the like; and a bindersuch as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose,cellulose derivatives or the like. In another solid dosage form, apowder, marume, solution or suspension (e.g., in propylene carbonate,vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulatedin a capsule (gelatin or cellulose base capsule). Unit dosage forms inwhich one or more compounds provided herein or additional active agentsare physically separated are also contemplated; e.g., capsules withgranules (or tablets in a capsule) of each drug; two-layer tablets;two-compartment gel caps, etc. Enteric coated or delayed release oraldosage forms are also contemplated.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.50 mg/kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.75 mg/kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.0 mg/kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.25 mg/kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.50 mg/kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.75 mg/kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 2.0 mg/kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 3.0 mg/kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 4.0 mg/kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 5.0 mg/kg to about 10 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I), isabout 0.1 μg/kg to about 10 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.1 μg/kg to about 5 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.2 μg/kg to about 9 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 μg/kg to about 8 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.3 μg/kg to about 7 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.4 μg/kg to about 6 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.5 μg/kg to about 5 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.6 μg/kg to about 5 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.0 μg/kg to about 4 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 2.0 μg/kg to about 4 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 3.0 μg/kg to about 5 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 4.0 μg/kg to about 6 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 5.0 μg/kg to about 10 μg/kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.01mg to 1 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.01mg to 0.5 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.01mg to 0.3 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.03mg to 0.9 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.03mg to 0.23 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.05mg to 0.8 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.07mg to 0.7 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.08mg to 0.7 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.1mg to 0.6 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.12mg to 0.6 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.14mg to 0.5 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.16mg to 0.5 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.18mg to 0.4 mg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.2mg to 0.4 mg in humans.

In some such embodiments, the pharmaceutical composition comprisesbetween about 0.005 mg/mL and 2.5 mg/mL of the compound of Formula (I),for example, between about 0.005 mg/mL to about 2 mg/mL, about 0.01mg/mL to about 1.8 mg/mL, about 0.025 mg/mL to about 1.6 mg/mL, about0.05 mg/mL to about 1.5 mg/mL, about 0.075 mg/mL to about 1.25 mg/mL,about 0.1 mg/mL to about 1 mg/mL, or about 0.25 mg/mL to about 0.75mg/mL. In some such embodiments, the pharmaceutical compositioncomprises about 0.015 mg/mL to about 0.115 mg/mL of the compound ofFormula (I). In some embodiments, the injection volume comprises betweenabout 0.1 mg/mL and 4 mg/mL. In some embodiments, the injection volumeis 2 mg/mL.

The compounds provided herein, e.g., compounds of Formula (I) can beformulated as a plurality of particles. For example, particles of acompound provided herein can have a median particle size of less than 20μm (e.g., less than about 15 μm; less than about 10 μm; less than about7.5 μm; less than about 5 μm; less than about 2.5 μm; less than about 1μm; and less than about 0.5 μm). For example, the median particle sizecan be between about 0.1 μm and 20 μm, such as between about 0.5-20,0.5-15, 0.5-10, 0.5-7.5, 0.5-5, 0.5-2.5, 0.5-1, 2.5-15, 5-10, 7.5-20, or1-5 μm. In some embodiments, the particles also comprise a polymer.Examples of suitable polymers include biocompatible and biodegradablepolymers like poly(lactic acid), a poly(glycolic acid), apoly(lactic-co-glycolic acid), a poly(lactide-co-glycolide), andmixtures thereof. In some embodiments, the particles comprisepoly(lactic-co-glycolic acid) (PLGA).

In some embodiments, the compound of Formula (I), a polymorph form ofCompound 10, e.g., Form 1, has a particle size distribution (D value),e.g., a D50, of between about 1 and about 6 μm, such as between about1.5 and about 5 μm, or about 2.4 to about 2.55 μm. For example, the D50can be about 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 4, 4.5, or 5 μm. In someembodiments, the D50 value is about 2.55 μm. In some embodiments, theD50 value is about 2.45 μm. In some embodiments, the D50 value is about2.1 μm. In some embodiments, the D50 value is about 2 μm. In someembodiments, the D50 value is about 1.6 μm. The D50 can be measured byconventional particle size measuring techniques well known to thoseskilled in the art. Such techniques include, for example, sedimentationfield flow fractionation, photon correlation spectroscopy, lightscattering, laser diffraction and disc centrifugation.

In one embodiment, the composition takes the form of a liquid. Liquidpharmaceutically administrable compositions can, for example, beprepared by dissolving, suspending or dispersing a compound providedherein and optional pharmaceutical adjuvants in a carrier (e.g., water,saline, aqueous dextrose, glycerol, glycols, ethanol or the like) toform a solution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of a compound provided herein contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thepatient. However, percentages of the compound of Formula (I), orpharmaceutically acceptable salt thereof, of 0.01% to 10% in solutionare employable, and could be higher if the composition is a solid orsuspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition comprises about 0.1-10% of thecompound of Formula (I) in solution. In some embodiments, thecomposition comprises about 0.1-5% of the compound of Formula (I) insolution. In some embodiments, the composition comprises about 0.1-4% ofthe compound of Formula (I) in solution. In some embodiments, thecomposition comprises about 0.15-3% of the compound of Formula (I) insolution. In some embodiments, the composition comprises about 0.2-2% ofthe compound of Formula (I) in solution. In some embodiments, thecompound of Formula (I) is Compound 10. In some embodiments, thecompound of Formula (I) is a polymorph form of Compound 10.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration of a dose. In some embodiments, thecompositions are provided in unit dosage forms suitable for twice a dayadministration of a dose. In some embodiments, the compositions areprovided in unit dosage forms suitable for three times a dayadministration of a dose.

Administration of the compounds and compositions disclosed herein, canbe via any of the accepted modes of administration, including, but notlimited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, ontologically,neuro-otologically, intraocularly, subconjuctivally, via anterior eyechamber injection, intravitreally, intraperitoneally, intrathecally,intracystically, intrapleurally, via wound irrigation, intrabuccally,intra-abdominally, intra-articularly, intra-aurally, intrabronchially,intracapsularly, intrameningeally, via inhalation, via endotracheal orendobronchial instillation, via direct instillation into pulmonarycavities, intraspinally, intrasynovially, intrathoracically, viathoracostomy irrigation, epidurally, intratympanically,intracisternally, intravascularly, intraventricularly, intraosseously,via irrigation of infected bone, or via application as part of anyadmixture with a prosthetic devices. In some embodiments, theadministration method includes oral or parenteral administration.

In some embodiments, the compositions containing a compound of Formula(I), or a pharmaceutically acceptable salt thereof, are provided indosage forms that are suitable for continuous dosage, e.g., byintravenous infusion, over a period of time, such as between about 1 and96 hours, e.g., between about 1-72, 1-48, 1-24, 1-12, or 1-6 hours. Insome embodiments, the compositions are provided in dosage forms suitablefor continuous dosage by intravenous infusion over a period of about1-96 hours. In some embodiments, the compositions are provided in dosageforms suitable for continuous dosage by intravenous infusion over aperiod of about 1-72 hours. In some embodiments, the compositions areprovided in dosage forms suitable for continuous dosage by intravenousinfusion over a period of about 1-48 hours. In some embodiments, thecompositions are provided in dosage forms suitable for continuous dosageby intravenous infusion over a period of about 1-24 hours. In someembodiments, the compositions are provided in dosage forms suitable forcontinuous dosage by intravenous infusion over a period of about 1-12hours. In some embodiments, the compositions are provided in dosageforms suitable for continuous dosage by intravenous infusion over aperiod of about 1-6 hours.

In some embodiments, the compositions containing a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be administered,such as by intravenous infusion, to a subject, e.g., a human, at a doseof between about 5 mg/m² and 300 mg/m², e.g., about 5 mg/m² to about 200mg/m², about 5 mg/m² to about 100 mg/m², about 5 mg/m² to about 100mg/m², about 10 mg/m² to about 50 mg/m², about 50 mg/m² to about 200mg/m², about 75 mg/m² to about 175 mg/m², or about 100 mg/m² to about150 mg/m². In some embodiments, these compositions can be administeredby intravenous infusion to humans at doses of about 5 mg/m² to about 300mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 200mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 100mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 10 mg/m² to about 50mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m². In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values can also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens can be adjusted over time according tothe individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In some embodiments, the compositions can be administered to therespiratory tract (including nasal and pulmonary), e.g., through anebulizer, metered-dose inhaler, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, for example, particle sizes of about 10 to about 60microns. For nasal delivery, a larger inhaled particle size may bedesired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For delivery to the lung,inhaled aerodynamic particle sizes of about less than 10 μm are useful(e.g., about 1 to about 10 microns). Inhaled particles can be defined asliquid droplets containing dissolved drug, liquid droplets containingsuspended drug particles (in cases where the drug is insoluble in thesuspending medium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, the compounds of Formula (I), includingpharmaceutically acceptable salts thereof, disclosed herein intended forrespiratory delivery (either systemic or local) can be administered asaqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates, or asdry powders. Aqueous formulations can be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems can use suitablepressurized metered-dose inhalers (pMDIs). Dry powders can use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution can beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I), includingpharmaceutically acceptable salts thereof, disclosed herein can beadministered to the ear by various methods. For example, a round windowcatheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the invention can be incorporated into a gelformulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I), includingpharmaceutically acceptable salts thereof, disclosed herein intended fordelivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments, the acidic or basic solid compound ofFormula (I), or pharmaceutically acceptable salt thereof, can bedelivered from the reservoir of an external or internal implantedpumping system.

Formulations provided herein can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815). Intratympanicinjection of a therapeutic agent is the technique of injecting atherapeutic agent behind the tympanic membrane into the middle and/orinner ear. In one embodiment, the formulations described herein areadministered directly onto the round window membrane via transtympanicinjection. In another embodiment, the ion channel modulating agentauris-acceptable formulations described herein are administered onto theround window membrane via a non-transtympanic approach to the inner ear.In additional embodiments, the formulation described herein isadministered onto the round window membrane via a surgical approach tothe round window membrane comprising modification of the cristafenestrae cochleae.

In some embodiments, the compounds of Formula (I), includingpharmaceutically acceptable salts thereof, are formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG (likePEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixing acompound provided herein with a suitable non-irritating excipient thatis solid at ordinary temperatures but liquid at the rectal temperatureand will therefore melt or erode/dissolve in the rectum and release thecompound. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, poloxamers, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter, is firstmelted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compoundprovided herein, the desired dissolution rate, cost considerations, andother criteria. In one of the embodiments, the solid composition is asingle unit. This implies that one-unit dose of the compound iscomprised in a single, physically shaped solid form or article. In otherwords, the solid composition is coherent, which is in contrast to amultiple unit dosage form, in which the units are incoherent.

Examples of single units which can be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In one embodiment, the solid composition is a highly porous lyophilizedform. Such lyophilizates, sometimes also called wafers or lyophilizedtablets, are particularly useful for their rapid disintegration, whichalso enables the rapid dissolution of the compound.

In some embodiments, the solid composition can be formed as a multipleunit dosage form as defined above. Examples of multiple units arepowders, granules, microparticles, pellets, mini-tablets, beads,lyophilized powders, and the like. In one embodiment, the solidcomposition is a lyophilized powder. Such a dispersed lyophilized systemcomprises a multitude of powder particles, and due to the lyophilizationprocess used in the formation of the powder, each particle has anirregular, porous microstructure through which the powder is capable ofabsorbing water very rapidly, resulting in quick dissolution.Effervescent compositions are also contemplated to aid the quickdispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with a compoundprovided herein so that the compound is located at the outer surface ofthe individual particles. In this type of system, the water-soluble lowmolecular weight excipient can be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, for example, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

The compounds and compositions provided herein can also be useful incombination (administered together or sequentially) with other knownagents. In some embodiments, a compound of Formula (I), orpharmaceutically acceptable salt thereof, can be used to treatinflammation in combination with any of the following: (a) nonsteroidalanti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirinand acetaminophen; (b) physical therapy; (c) narcotics, like codeine;and (d) in combination with a chronic pain class.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient).

5. Methods of Treatment

Provided are methods for treating a disease or disorder associated withinflammation. The method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In some embodiments, the methods are effective fortreating an inflammatory disease or disorder of an animal. In someembodiments, the methods are effective for treating an inflammatorydisease or disorder of a mammal. In some embodiments, the mammal is ahuman.

Diseases and disorders associated with inflammation that can be treatedby the methods described herein include, but are not limited to,achalasia, acne vulgaris, allergy and allergic responses toenvironmental stimuli such as poison ivy, pollen, insect stings andcertain foods, Alzheimer's disease, amyloidosis, angina, (anginapectoris), ankylosing spondylitis, appendicitis, asthma, atheroscleroticcardiovascular disease (atherosclerosis, ASVD), autoimmune diseases,auto inflammatory diseases, bradycardia (bradyarrhythmia),cancer-related inflammation, cardiac hypertrophy (heart enlargement),celiac disease, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), chronic prostatitis, cirrhosis, colitis, dermatitis(including contact dermatitis and atopic dermatitis), diabetes,diverticulitis, endothelial cell dysfunction, endotoxic shock (septicshock), fibrosis, glomerulonephritis, hemolytic-uremia, hepatitis, HIVand AIDS, hidradenitis suppurativa, hypersensitivities, hypertension,inflammatory bowel disease, Crohn's disease, interstitial cystitis,intimal hyperplasia, ischemia, leukocyte defects (including but notlimited to Chediak-Higashi syndrome and chronic granulomatous diseasessuch as tuberculosis, leprosy, sarcoidosis, and silicosis), localizedinflammatory disease, lung inflammation, lupus, migraine, morphea,myopathies, nephritis, oncological disease (including, but not limitedto, epithelial-derived cancers such as, but not limited to, breastcancer and prostate cancer), orbital inflammatory disease, IdiopathicOrbital Inflammatory Disease, pain, pancreatitis, pelvic inflammatorydisease, polymyositis, post-infection inflammation, Prinzmetal's angina(variant angina), psoriasis, pulmonary hypertension, Raynaud'sdisease/phenomenon, Reiter's syndrome, renal failure, reperfusioninjury, rheumatic fever, rheumatoid arthritis, osteoarthritis,sarcoidosis, scleroderma, Sjogren's syndrome, smooth muscle cell tumorsand metastasis (including leiomyoma), smooth muscle spasm, stenosis,stroke, thrombotic disease, toxemia of pregnancy, tendinopathy,transplant rejection, ulcers, vasculitis, and vasculopathy.

In some embodiments, diseases and disorders associated with inflammationthat can be treated by the methods described herein include poison ivy,Alzheimer's disease, ankylosing spondylitis, autoimmune diseases, autoinflammatory diseases, cancer-related inflammation, chronic obstructivepulmonary disease (COPD), colitis, dermatitis (including contactdermatitis and atopic dermatitis), diabetes, diverticulitis, endotoxicshock (septic shock), fibrosis, hidradenitis suppurativa, inflammatorybowel disease, Crohn's disease, intimal hyperplasia, localizedinflammatory disease, lupus, morphea, orbital inflammatory disease,Idiopathic Orbital Inflammatory Disease, pelvic inflammatory disease,psoriasis, Raynaud's disease/phenomenon, rheumatoid arthritis,osteoarthritis, scleroderma, Sjogren's syndrome, tendinopathy,transplant rejection, ulcers, vasculitis, and vasculopathy.

In some embodiments, diseases and disorders associated with inflammationthat can be treated by the methods described herein include poison ivy,ankylosing spondylitis, auto inflammatory diseases, cancer-relatedinflammation, colitis, dermatitis (including contact dermatitis andatopic dermatitis), diverticulitis, hidradenitis suppurativa, Crohn'sdisease, intimal hyperplasia, morphea, orbital inflammatory disease,Idiopathic Orbital Inflammatory Disease, pelvic inflammatory disease,Raynaud's disease/phenomenon, tendinopathy, ulcers, and vasculopathy.

In some embodiments, diseases and disorders associated with inflammationthat can be treated by the methods described herein do not includeAlzheimer's disease, autoimmune diseases, chronic obstructive pulmonarydisease (COPD), diabetes, endotoxic shock (septic shock), fibrosis,inflammatory bowel disease, localized inflammatory disease, lupus,psoriasis, rheumatoid arthritis, osteoarthritis, scleroderma, Sjogren'ssyndrome, transplant rejection, and vasculitis

In some embodiments, the inflammatory disease or disorder is chronicinflammation associated with a disease or condition, including, but notlimited to, asthma, chronic peptic ulcer, tuberculosis, rheumatoidarthritis, chronic periodontitis, ulcerative colitis and Crohn'sdisease, chronic sinusitis, and chronic active hepatitis.

In some embodiments, the inflammatory disease or disorder is anautoinflammatory disease. Exemplary auto inflammatory diseases include,but are not limited to, familial Mediterranean fever (FMF); tumornecrosis factor receptor-associated periodic syndrome (TRAPS);deficiency of the interleukin-1 receptor antagonist (DIRA); Behcet'sdisease; mevalonate kinase deficiency (MKD, also known as hyper IgDsyndrome (HIDS)); periodic fever, aphthous stomatitis, pharyngitis, andcervical adenitis (PFAPA, also known as Marshall syndrome); Majeedsyndrome; chronic recurrent multifocal osteomyelitis (CRMO); pyogenicarthritis, pyoderma gangrenosum, and cystic acne (PAPA); Schnitzlersyndrome; Blau syndrome (NOD2, also known as pediatric granulomatousarthritis (PGA) or juvenile sarcoidosis); NLRP12 associatedautoinflammatory disorders (NLRP12AD); chronic atypical neutrophilicdermatosis with lipodystrophy and elevated temperature (CANDLE)syndrome; systemic juvenile idiopathic arthritis (SJIA); andcryopyrin-associated periodic syndromes (CAPS), including familial coldautoinflammatory syndrome (FACS), Muckle-Wells syndrome, andneonatal-onset multisystem inflammatory disease (NOMID).

In some embodiments, the disease or disorder associated withinflammation is tuberculosis.

In some embodiments, the disease or disorder associated withinflammation is systemic inflammation.

In some embodiments, the disease or disorder associated withinflammation is rheumatoid arthritis.

In some embodiments, the disease or disorder associated withinflammation is lung inflammation.

In some embodiments, the disease or disorder associated withinflammation is COPD.

In some embodiments, the disease or disorder associated withinflammation is chronic bronchitis.

In some embodiments, the one or more diseases or conditions ispsoriasis. Non-limiting examples include: psoriasis vulgaris (includingnummular psoriasis and plaque psoriasis); generalized pustular psoriasis(including impetigo herpetiformis and von Zumbusch's disease);acrodermatitis continua; pustulosis palmaris et plantaris; guttatepsoriasis; arthropathic psoriasis; other psoriasis (including inversepsoriasis).

In some embodiments, the one or more diseases or conditions isdermatitis. Non-limiting examples include: atopic dermatitis, contactdermatitis (e.g., allergic contact dermatitis, irritant contactdermatitis), stasis dermatitis, dermatitis that led up to steroiddermatitis, steroid-resistant dermatitis, dermatitis to which tacrolimusis not applicable, chronic dermatitis, erythroderma (e.g., erythrodermaposteczematosa and erythroderma secondary to dermatoses, toxicerythroderma, infantile desquamative erythroderma, and paraneoplasticerythroderma), eczema, nummular eczema, dyshidrotic eczema, asteatoticeczema, seborrheic dermatitis, autosensitization dermatitis, stasisdermatitis, urticaria, drug eruption, dermal vasculitis, prurigo,pruritus cutaneus, erythema (e.g. nodosum or multiforme), rosacea,rosacea-like dermatitis, lichen planus, photo-induced dermatitis, orfollicular keratosis. In certain embodiments, the dermatitis is contactdermatitis, e.g., allergic contact dermatitis, e.g., resulting fromdirect skin contact with a substance such as poison ivy, poison oak, orpoison sumac.

In some embodiments, the tendinitis is selected from the groupconsisting of biceps tendinitis, triceps tendinitis, extensor carpiradialis brevis tendinitis, common extensor tendinitis, extensordigitorum tendinitis, extensor digiti minimi tendinitis, extensor carpiulnaris tendinitis, supinator tendinitis, common flexor tendinitis,pronator teres tendinitis, flexor carpi radialis tendinitis, palmarislongus tendinitis, flexor carpi ulnaris tendinitis and digitorumsuperficialis tendinitis. In some embodiments, the tendinitis isselected from the group consisting of biceps tendinitis, tricepstendinitis, extensor carpi radialis brevis tendinitis, common extensortendinitis, extensor digitorum tendinitis, extensor digiti minimitendinitis, extensor carpi ulnaris tendinitis, supinator tendinitis,common flexor tendinitis, pronator teres tendinitis, flexor carpiradialis tendinitis, palmaris longus tendinitis, flexor carpi ulnaristendinitis, digitorum superficialis tendinitis, flexor pollicis brevistendinitis, flexor pollicis longus tendinitis, abductor pollicis brevistendinitis, abductor pollicis longus tendinitis, flexor digitorumprofundus tendinitis, flexor digitorum superficialis tendinitis,extensor pollicis brevis tendinitis, and extensor pollicis longustendinitis. In some embodiments, the tendinitis is selected from thegroup consisting of flexor pollicis brevis tendinitis, flexor pollicislongus tendinitis, abductor pollicis brevis tendinitis, abductorpollicis longus tendinitis, flexor digitorum profundus tendinitis,flexor digitorum superficialis tendinitis, extensor pollicis brevistendinitis, calcific tendinitis, and extensor pollicis longustendinitis.

In some embodiments, the tendinitis is caused by chronic overuseinjuries of tendon failed healing.

In some embodiments, provided are methods for treating a disease ordisorder associated with inflammation in a patient comprisingadministration to a patient a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutical compositionis a suspension. In some embodiments, the pharmaceutical composition isa solution. In some embodiments of the method provided herein, thecompound of Formula (I) is Compound 10. In some embodiments, thecompound of Formula (I) is a polymorph form of Compound 10.

In some embodiments of the methods provided herein, the compound ofFormula (I), including pharmaceutically acceptable salts thereof,inhibits one or more cytokines. In some embodiments, the cytokines areproinflammatory cytokines. Exemplary proinflammatory cytokines include,but are not limited to, IL-1α, IL-1β, IL-6, IL-8, IL-17, IL-18, IL-23,IFN-α, IFN-γ, TNF-α, HMG-1, and macrophage migration inhibitory factor(MIF). Proinflammatory cytokines are to be distinguished fromanti-inflammatory cytokines, such as IL-4, IL-10, and IL-13, which arenot mediators of inflammation.

Proinflammatory cytokines are often produced in an inflammatory cytokinecascade, which is an in vivo release of at least one proinflammatorycytokine in a mammal, wherein the cytokine release, directly orindirectly (e.g., through activation of, production of, or release of,one or more cytokines or other molecules involved in inflammation from acell), stimulates a physiological condition of the mammal. In someembodiments of the methods described herein, an inflammatory cytokinecascade is inhibited where the release of proinflammatory cytokinescauses a deleterious physiological condition, such as a disease ordisorder associated with inflammation described elsewhere herein.

In some embodiments, the method treats a disease or disorder mediated bycytokine activity in a patient, comprising administering to a patient atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. In some embodiments, themethod comprises administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In some embodiments, the compound of Formula (I) isCompound 10. In some embodiments, the compound of Formula (I) is apolymorph form of Compound 10.

In some embodiments, the methods provided herein result in a decrease inthe amount of a biomarker linked to inflammation in a patient. In someembodiments, the methods provided herein result in a decrease inproinflammatory cytokines in a patient as assessed by any of the methodsdescribed herein and known to those of skill in the art. For example, adecrease in the amount of a biomarker linked to inflammation can bedetermined by a blood test or a urine test. For example, the decrease inthe amount of biomarker in a sample from a patient is about 10% to about100%. In some embodiments, the decrease in the amount of biomarker in asample from a patient is about 30% to about 100%. For example, thedecrease in the amount of biomarker in a sample from a patient is about40% to about 100%, about 50% to about 100%, about 60% to about 100%,about 70% to about 100%, about 80% to about 100%, about 90% to about100%, about 25% to about 75%, about 40% to about 80%, or about 50% toabout 75%.

In some embodiments, the biomarker is a proinflammatory cytokine. Insome embodiments, the biomarker is IL-1β. In some embodiments, thebiomarker is IL-6. In some embodiments, the biomarker is IL-8. In someembodiments, the biomarker is IL-17. In some embodiments, the biomarkeris L-21. In some embodiments, the biomarker is IL-23. In someembodiments, the biomarker is IFN-γ. In some embodiments, the biomarkeris TNF-α.

In some embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is administered to a patient in need thereof inan amount sufficient to inhibit the release of one or moreproinflammatory cytokines from a cell and/or to treat a disease ordisorder associated with inflammation. In one embodiment, release of theproinflammatory cytokine is inhibited by at least 10%, 20%, 25%, 50%,75%, 80%, 90%, or 95%, over non-treated controls, as assessed usingmethods described herein or other methods known in the art. In someembodiments, the compound of Formula (I) is Compound 10. In someembodiments, the compound of Formula (I) is a polymorph form of Compound10.

In some embodiments, the method comprises administering to a patient apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, once daily. In someembodiments, administration is more than one time a day. In someembodiments, administration is two, three, four or more times a day.

In some embodiments of the methods provided herein, a pharmaceuticalcomposition provided herein delivers a therapeutically effectiveconcentration of the compound of Formula (I) to the joint surroundingthe site of administration for at least about two weeks followingadministration. For example, the pharmaceutical composition can providea therapeutically effective concentration of the compound of Formula (I)in the joint surrounding the site of administration for at least about30 days following administration. In some embodiments, thepharmaceutical composition provides a therapeutically effectiveconcentration of the compound of Formula (I) in the joint surroundingthe site of administration for at least about 45 days followingadministration. In some embodiments, the pharmaceutical compositionprovides a therapeutically effective concentration of the compound ofFormula (I) in the joint surrounding the site of administration for atleast about 60 days following administration. In some embodiments, thepharmaceutical composition provides a therapeutically effectiveconcentration of the compound of Formula (I) in the joint surroundingthe site of administration for at least about 90 days followingadministration. For example, the pharmaceutical composition can providea therapeutically effective concentration of the compound of Formula (I)in the joint surrounding the site of administration for at least about180 days following administration. In some embodiments, the compound ofFormula (I) is radiolabeled before administration. In some embodiments,the compound of Formula (I) is radiolabeled with tritium (³H). Theconcentration of the radiolabeled compound of Formula (I) can bemeasured in the plasma by detection methods known to those of skill inthe art. For example, the radiolabeled compound of Formula (I) can bemeasured by quantitative radiochemical analysis (QRA). In someembodiments, the radiolabeled compound of Formula (I) is measured byquantitative whole body autoradiography (QWBA). In some embodiments, theradiolabeled compound of Formula (I) is detected by radiographicimaging. In some embodiments, the compound of Formula (I) in thecomposition comprises Form 1. In some embodiments, the compound ofFormula (I) in the composition comprises a non-stoichiometric hydrate ofForm 1 having between 1% and about 20% by weight water. In someembodiments, the compound of Formula (I) in the composition issubstantially present as a non-stoichiometric hydrate of Form 1 havingbetween 1% and about 20% by weight water. In some embodiments, thepharmaceutical composition is a solution. In some embodiments, thepharmaceutical composition is a suspension.

In some embodiments of the methods provided herein, the compositions areformulated such that the compound of Formula (I), e.g., Compound 10,e.g., Form 1, is bioavailable over an extended period of time followingadministration. In some embodiments, the compound of Formula (I)maintains a concentration within a therapeutic window for a desiredperiod of time.

In some embodiments, the compositions comprising a compound of Formula(I) provided herein are administered once. In some embodiments, thecompositions comprising a compound of Formula (I) are administered morethan once. In some embodiments, the composition is administered in dosesspaced at least 4 weeks apart (e.g., at least 6 weeks apart, at least 8weeks apart, at least 12 weeks apart). For example, the composition isadministered in doses spaced at least 3 months apart up to about 60months apart. In some embodiments, the composition is administered onceevery 3 months. In some embodiments, the composition is administeredonce every 6 months. In some embodiments, the composition isadministered once every 12 months. In some embodiments, the compositionis administered once every 24 months. In some embodiments, thecomposition is administered once every 60 months.

In some embodiments, the methods can further include administering oneor more other therapeutic regimens and/or agents effective for treatingan inflammatory disease or a disease or disorder associated withinflammation, e.g., palliative care, with treatment focusing onanti-inflammatory measures, including treatment with nonsteroidalanti-inflammatory drugs (NSAIDs), steroid injections, topical steroids,cortisone injections, and topical cortisone.

Also provided herein are methods of treating a patient that includefirst assessing the severity of the disease or disorder associated withinflammation in the patient and then administering to the patient a doseof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, based on the assessment. Inflammation can be assessed by anymethod known to those of skill in the art, including, but not limitedto, blood and urine tests to measure and test for biomarkers linked toinflammation, such as serum proteins associated with inflammation,antinuclear antibodies (ANAs), double stranded DNA (dsDNA), C-reactiveprotein (CRP), rheumatoid factor, cyclic citrullinated peptide (CCP)antibody, erythrocyte sedimentation rate (ESR), F2-isoprostanes(F2-IsoPs), oxidized LDL (OxLDL), myeloperoxidase (MPO), plasmaviscosity (PV), proinflammatory cytokines, and any combination thereof;evaluation of the amount of swelling and pain in joints; x-rays, and anycombination thereof.

In some embodiments, the presence or levels of any one or anycombination of cytokine biomarkers can be used to select a patient withacute joint injury for treatment. In some embodiments, the cytokinebiomarkers are proinflammatory cytokines. In some embodiments, theproinflammatory cytokines are selected from the group consisting ofIL-1α, IL-1β, IL-2, L-4, L-5, L-6, L-7, IL-8, IL-10, IL-12/IL23p40,IL-13, IL-15, L-16, IL-17A, IL-17F, TNFα, TNF-β, IFN-γ, CXCL1, CD38,CD40, CD69, IgG, IP-10, L-17A, MCP-1, PGE2, sIL-2, and sIL-6. [0401]. Insome embodiments, the proinflammatory cytokines can be used to diagnoseinflammation or a disease or disorder associated with inflammation. Insome embodiments, the presence or level of these cytokine biomarkers,e.g., proinflammatory cytokines, can be used to select a patient as acandidate for treatment. In some other embodiments, the presence orlevels of the cytokine biomarkers can be used to determine the successduring the course of or after treatment of a disease or disorderassociated with inflammation.

5. Evaluation of Biological Activity

The biological activity of the compounds described herein and used inthe provided methods can be tested using any suitable assay known tothose of skill in the art. See, e.g., WO 2001/053268 and WO 2005/009997,both of which are incorporated by reference in their entirety, and theExamples, below.

The expression of a biomarker linked to inflammation, such as aproinflammatory cytokine, can be assessed by any method known to thoseof skill in the art. Biomarkers can be detected by any method known tothose of skill in the art, including, but not limited to, blood andurine tests to measure and test for biomarkers linked to inflammation,such as serum proteins associated with inflammation, antinuclearantibodies (ANAs), double stranded DNA (dsDNA), C-reactive protein(CRP), rheumatoid factor, cyclic citrullinated peptide (CCP) antibody,erythrocyte sedimentation rate (ESR), F2-isoprostanes (F2-IsoPs),oxidized LDL (OxLDL), myeloperoxidase (MPO), plasma viscosity (PV),proinflammatory cytokines, and any combination thereof; evaluation ofthe amount of swelling and pain in joints; x-rays, and any combinationthereof. In some embodiments, the biomarker detection methods areperformed before, during, or after, or any combination thereof,administering the compounds provided herein that decrease the amount ofbiomarker associated with inflammation.

Immunoassays can be used to qualitatively or quantitatively analyze thecytokine biomarker levels, e.g., the levels of IFN-γ, IL-10,IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17C,IL-17E/IL-25, IL-17F, IL-1β, IL-2, IL-21, IL-22, IL-23, IL-27p28/IL-30,IL-31, IL-33, IL-4, IL-5, IL-6, KC/GRO, VEGF-A, and TNF-α in abiological sample. See, e.g., Harlow & Lane, Cold Spring HarborLaboratory Press, Using Antibodies: A Laboratory Manual (1999) for ageneral overview of the technology.

In addition to using immunoassays to detect the levels of cytokines in abiological sample, assessment of cytokine expression and levels can bemade based on the level of gene expression of a particular cytokine. RNAhybridization techniques for determining the presence and/or level ofmRNA expression are well known to those of skill in the art and can beused to assess the presence or level of gene expression of the cytokinebiomarkers of interest.

Other methods of assessing the levels of cytokines in a biologicalsample include, but are not limited to, immunofluorescence,immunoturbidimetry, immunonephelometry, high resolution serum proteinelectrophoresis, ELISA, Q-PCR, and intracellular cytokine stainingdetected by FACS. In some embodiments, expression of a biomarker can bedetected via fluorescent based readouts on a cell culture performedusing an antibody specific for the biomarker or molecule associatedthereto, labeled with fluorophore, which includes, but not exhaustively,small molecular dyes, protein chromophores, quantum dots, and goldnanoparticles. In some embodiments, expression of a biomarker can bedetected by detecting expression of a label under the transcriptionalcontrol of a biomarker promoter in vivo (e.g., in an animal tissue) orin vitro (e.g. in a cell culture). Additional techniques will be knownto those of skill in the art.

Additional assays for inflammation include utilizing cells such as THP-1monocytes, RAW264.7 macrophages, M1, M2 macrophage polarization, PBMCs,T cells, B cells, Jurkat cells, synovial fibroblasts, splenocytes, T regcells and other types of systemic or tissue resident immune cells. Insome embodiments, the cells can be assayed in the presence of variousstimulators, such as LPS, PMA+ionomycin, CD3-CD28, IL-3, calcimycin,TNF-α, IgM, super-antigen, Concanavalin A, and any other stimulationthat activates immune cells. See, for example, Chanput W, et. al.,Transcription profiles of LPS-stimulated THP-1 monocytes andmacrophages: a tool to study inflammation modulating effects offood-derived compounds., Food Funct. 2010 December; 1(3):254-61; Park EK, et. al., Optimized THP-1 differentiation is required for thedetection of responses to weak stimuli. Inflamm Res. 2007 January;56(1):45-50; Anta Ngkelo, et. al., LPS induced inflammatory responses inhuman peripheral blood mononuclear cells is mediated through NOX4 andGia dependent PI-3kinase signaling, Journal of Inflammation 20129:1;Wenchao Ai, et. al., Optimal Method to Stimulate Cytokine Production andIts Use in Immunotoxicity, Assessment Int J Environ Res Public Health.2013 September; 10(9): 3834-3842; K Sperber, et. al., Cytokine secretioninduced by superantigens in peripheral blood mononuclear cells, laminapropria lymphocytes, and intraepithelial lymphocytes., Clin Diagn LabImmunol. 1995 July; 2(4): 473-477; Monner D A, et. al., Induction oflymphokine synthesis in peripheral blood mononuclear cells with phorbolester and calcium ionophore allows precise measurement of individualvariations in capacity to produce IL 2, Lymphokine Res. 1986; 5 Suppl1:S67-73; Ikejima T, et. al., Interleukin-1 induces tumor necrosisfactor (TNF) in human peripheral blood mononuclear cells in vitro and acirculating TNF-like activity in rabbits. J Infect Dis. 1990 July;162(1):215-23; and B D Gitter, et. al., Characteristics of humansynovial fibroblast activation by IL-1 beta and TNF alpha. Immunology,February 1989; 66(2): 196-200.

EXAMPLES Example 1: Polymorph Screen

A polymorph screen was performed on the compound of Formula (I) todetermine solubility, polymorphism, and thermodynamic stability.

A. Analysis of the Starting Solid (a Mixture of Form 1 and aNon-Stoichiometric Hydrate of Form 1)

X-ray powder diffraction (XRD), differential scanning calorimetry (DSC),and thermal gravimetric analysis (TGA) scans of the starting solidcompound of Formula (I), indicated that the starting solid was acrystalline material and was a mixture of Form I and anon-stoichiometric hydrate of Form 1 having between 1% and about 20% byweight water. According to the DSC scan (FIG. 12B), the solid showed awide endotherm between 50° C.-100° C.; it also showed a sharp exothermat 284° C.; and the solid eventually melted at 364° C. According to theTGA scan (FIG. 12C), a 1.4% weight loss was observed before 100° C.

The solubility of the mixture of Form 1 and a non-stoichiometric hydrateof Form 1 was measured by the gravimetric method and indicated that thecompound had low solubility at RT and at 50° C. in all solvents testedexcept DMF and DMSO. Results from the solubility data test at RT and at50° C. are shown in Table 2.

TABLE 2 Solubility data of the starting solid (a non-stoichiometric orstoichiometric hydrate of Form 1) Solubility at RT Solubility at 50° C.Solvents (mg/mL) (mg/mL) Acetone 1 1 Acetonitrile ~0 0 MeOH 1 1 Toluene1 1 EtOH 2 2 IPAc ~0 ~0 EA 1 1 MtBE ~0 ~0 IPA 2 5 MEK 1 1 MA ~0 ~0n-Propanol 1 2 MIBK 1 1 n-Butyl acetate ~0 ~0 water 1 1 Heptane ~0 ~0n-Butanol 1 2 DMSO n/a n/a DMF 12 16 DCM 2 2 Acetic acid ~0 3

Slurry experiments in various solvents were performed. Approximately30-80 mg of the starting solid (a non-stoichiometric hydrate of Form 1having between 1% and about 20% by weight water) was slurried in 39different solvents (pure and binary solvents; the ratio of organicsolvent/water (V/V) was 95%/5%) at RT and 50° C. for 5 days. Threesolvates, one non-stoichiometric hydrate, and eleven non-solvated formswere identified. A “*” after a particular Form, e.g., Form 2*, indicatesthat the forms had similar XRD scans with minor differences and wereconsidered to belong to the same class. Generally, the identified formsshowed multiple endotherms/exotherms on differential scanningcalorimetry (DSC) scans; Form 9 showed a single endotherm. XRD of bothwet and dry samples were scanned (FIG. 12A (dry sample)). The data isshown in Tables 3 and 4 below.

TABLE 3 Results of slurry experiments at RT Crystalline Form CrystallineForm Solvent (wet/dry) Solvent (wet/dry) Acetone Solvate 1 Form 2Acetone/ Solvate 2 Form 4** water Aceto- Form 2 Form 1 Acetonitrile/Form 12 Form 1 nitrile water MeOH Form 13 Form 1 MeOH/water Form 12 Form1 Toluene Form 1 Form 2* Toluene/ Form 13 Form 1 water EtOH Form 2* Form3 EtOH/water Solvate 3 Form 2 IPAc Form 3 Form 4 IPAc/water Form 12 Form1 EA Form 4* Form 5 EA/water Form 12 Form 1 MtBE Form 5* Form 6MtBE/water Form 12 Form 1 IPA Form 6 Form 7 IPA/water Form 6 Form 6 MEKForm 7 Form 4 MEK/water Form 7 Form 7 MA Form 4 Form 4* MA/water Form 13Form 1 n- Form 4* Form 8 n-Propanol/ Form 2** Form 2** Propanol waterMIBK Form 8 Form 3 MIBK/water Form 12 Form 1 n-Butyl Form 3* Form 1n-Butyl Form 13 Form 12 acetate acetate/water Water Form 13 Form 1Heptane/ Form 13 Form 12 water Heptane Form 1 Form 9 n-Butanol/ Form 13Form 13 water n-Butanol Form 9 Form 10 DMSO/water amor- Form 10 phousDMSO amor- Form 11 DMF/water Form 11 Form 11 phous DMF Form 11 Form 1DCM/water Form 13 Form 1 DCM Form 1 Form 2

TABLE 4 Results of slurry experiments at 50° C. Crystalline FormCrystalline Form Solvent (wet/dry) Solvent (wet/dry) Acetone Solvate 2Form 4** Acetone Form 4** Form 4** /water Aceto- Form 2* Form 2Acetonitrile/ Form 13 Form 13 nitrile water MeOH Form 1 Form 1MeOH/water Form 13 Form 13 Toluene Form 1 Form 1 Toluene/ Form 13 Form13 water EtOH Form 2* Form 2* EtOH/water Form 9 Form 9 IPAc Form 9 Form9 IPAc/water Form 13 Form 13 EA Form 4* Form 4 EA/water Form 4* Form 4*MtBE Form 5* Form 4 MtBE/water Form 13 Form 13 IPA Form 6 Form 6IPA/water Form 6 Form 6 MEK Form 7 Form 7 MEK/water Form 7 Form 7 MAForm 4 Form 4 MA/water Form 12 Form 4 n- Form 4 Form 4** n-Propanol/Form 9 Form 9 Propanol water MIBK Form 8 Form 8 MIBK/water Form 13 Form1 n-Butyl Form 9 Form 9 n-Butyl Form 13 Form 1 acetate acetate/waterwater Form 13 Form 13 Heptane/ Form 13 Form 1 water Heptane Form 13 Form13 n-Butanol/ Form 13 Form 1 water n-Butanol Form 9 Form 9 DMSO/waterAmor- Form 10 phous DMSO Amor- Form 10* DMF/water Form 11 Form 11 phousDMF Form 11 Form 11* DCM/water Form 13 Form 1 DCM Form 13 Form 13

The slurry experiments identified 3 solvated forms from wet samples(Solvates 1, 2, and 3); 2 non-stoichiometric hydrates of Form 1 (Forms12 and 13); and 11 non-solvated forms (Forms 1-11). In some instances,similar XRD scans with minor differences were obtained. These wereconsidered to be part of the same class (e.g., the same form). Forexample, XRD scans of Form 2 and Form 2* were similar and wereconsidered to belong to the same class. The solvated forms were obtainedfrom wet sample analysis; after drying, the sample indicated a differentXRD.

Solvate 1 was obtained from acetone at RT, and after drying, a lowcrystallinity solid was generated. Solvate 2 was obtained from acetone(at RT) and acetone/water (at RT), and after drying, Form 4** wasgenerated. Solvate 3 was obtained from EtOH/water at RT, and afterdrying, Form 2 was generated.

B. Form 1

The experiments that generated Form 1 are shown in Table 5, below. Form1 was generally obtained from drying of Form 13 or Form 12. Form 1 maybe considered as a dehydrated hydrate. Reslurry in many binary solvents(with 5% water) generated Form 1. Purity of the residual solid was98.9%. KF of Form 1 (one sample) solid was 5.8%; residual MeOH of Form 1solid was 0.01%. A TGA scan of fully dried Form 1 solid was performed(FIG. 1C). A 0.33% weight loss was observed before 100° C.

Form 1 showed sharp crystalline peaks on the XRD scan (FIG. 1A). The XRDpeaks of Form 1 are shown in Table 6, below. According to the DSC scan(FIG. 1B), the solid showed a wide endotherm between 50-100° C.; itshowed a sharp exotherm at 281° C.; and the melting point was 363° C.

The Form 1 solid was dried at 75° C. under vacuum overnight, and XRD,DSC, and TGA scans were performed. Comparison of the first and thesecond XRD scans (after drying at 75° C. under vacuum overnight), showedno change. However, the DSC scans indicated the absence of endotherm.The loss of the early peak on the DSC scan had no effect on the XRDtrace, showing that the wide endotherm between 50-100° C. on DSC scanwas due to the free solvent.

The Form 1 solid was heated in a DSC chamber to 305° C. (past theendotherm/exotherm around 280° C.), and then scanned by XRD. Comparisonof the first and the third XRD and DSC scans shows that after heating to305° C., Form 1 converted to Form 9. It can be concluded that theendotherm/exotherm around 280° C. might be due tomelting/crystallization events.

Form 1 tended to convert to a non-stoichiometric hydrate of Form 1having between 1% and about 20% by weight water at RH above 40-50%. Thehydrate lost its water below 30% RH. Form 1 converts to anon-stoichiometric hydrate of Form 1 when exposed to air.

The dynamic vapor sorption (DVS) scan of Form 1 solid showed a 17% waterabsorption at 90% RH (FIG. 1D). The XRD data indicated that the solidused in the DVS test converted to the hydrate form before the start ofthe DVS test. However, at 0% RH, water was lost, perhaps indicating thatthe solid was Form 1.

TABLE 5 Summary of experiments that generated Form 1 Form SolventTemperature Wet Dry Form 1 MeOH RT Form 13 Form 1 MeOH 50° C. Form 1Form 1 Toluene RT Form 1 Form 1 Toluene 50° C. Form 1 Form 1 water RTForm 13 Form 1 Heptane RT Form 1 Form 1 DCM RT Form 1 Form 1Acetonitrile/water RT Form 12 Form 1 MeOH/water RT Form 12 Form 1Toluene/water RT Form 13 Form 1 IPAc/water RT Form 13 Form 1 EA/water RTForm 12 Form 1 MtBE/water RT Form 12 Form 1 MA/water RT Form 13 Form 1MIBK/water RT Form 12 Form 1 MIBK/water 50° C. Form 13 Form 1 DCM/waterRT Form 13 Form 1 DCM/water 50° C. Form 13 Form 1 n-Butyl acetate/water50° C. Form 13 Form 1 Heptane/water 50° C. Form 13 Form 1n-Butanol/water 50° C. Form 13 Form 1 *Amount of water in binarysolvents is 5%

TABLE 6 XRD peaks of Form 1 2-Theta d(A) BG Height I % Area I % FWHM5.778 15.2835 57 97 28.3 1765 18.5 0.309 6.801 12.9871 19 343 100 830687.1 0.412 9.26 9.5427 20 178 51.9 3884 40.7 0.371 12.421 7.1203 30 23167.3 4862 51 0.358 13.919 6.357 35 147 42.9 3668 38.5 0.424 14.5016.1033 40 133 38.8 3439 36.1 0.44 16.5 5.3681 47 196 57.1 4286 44.90.372 17.26 5.1333 53 46 13.4 560 5.9 0.207 18.52 4.7868 68 342 99.79539 100 0.474 19.161 4.6282 54 215 62.7 4130 43.3 0.327 20.302 4.370649 133 38.8 2823 29.6 0.361 20.619 4.304 43 80 23.3 2047 21.5 0.43523.056 3.8543 41 38 11.1 765 8 0.342 24.642 3.6098 33 175 51 7235 75.80.703 25.302 3.5171 86 80 23.3 2345 24.6 0.498 26.1 3.4113 83 69 20.11545 16.2 0.381 27.46 3.2453 52 46 13.4 872 9.1 0.322 28.739 3.1038 3984 24.5 2146 22.5 0.434 30.444 2.9337 34 32 9.3 1080 11.3 0.54 33.3022.6882 30 27 7.9 683 7.2 0.405

C. Forms 2, 2*, and 2***

The experiments that generated Forms 2, 2*, and 2** are shown in Table7, below. XRD scans of Forms 2, 2* and 2** were performed (FIGS. 2A, 2D,and 2G show the XRD scans of Forms 2, 2*, and 2**, respectively). TheXRD peaks of Forms 2 and 2* are shown in Tables 8 and 9, below,respectively. DSC scans were also performed (FIGS. 2B, 2E, and 2H showthe DSC scans of Forms 2, 2*, and 2**, respectively). According to theDSC scans, Forms 2, 2* and 2** each showed a wide endotherm between 50°C.-100° C., and multiple endotherms and exotherms before melting at 363°C. The wide endotherm before 100° C. may be due to the containment ofwater/solvent in the solid. Form 2 was obtained from acetonitrile; Form2* from ethanol; Form 2** from n-propanol/5% water.

A TGA scan of Form 2 (FIG. 2C) showed a 2.7% weight loss before 116° C.FIG. 2F shows the TGA scan of Form 2*

A PLM photo of Form 2 was taken, indicating that the particle size ofthis solid was around 50 um.

The Form 2 solid was heated in a DSC machine to 90° C. (past the wideendotherm between 50-100° C.); to 270° C. (past the endotherm/exothermaround 240° C.); and finally to 330° C. (past the exotherm around 330°C.). The residual solid was analyzed by XRD. According to the first andsecond XRD and DSC scans, the form did not change before and afterheating to 90° C. The wide endotherm between 50-100° C. might be freesolvent or hydrate. According to the first and third XRD and DSC scans,after heating a Form 2 sample to 270° C., the solid converted to lowcrystalline solids. According to the first and fourth XRD and DSC scans,after heating the sample to 330° C., the solid converted to Form 9.Thus, the exotherm around 290° C. was a re-crystallization event.According to an XRD and DSC overlay, the behavior of Form 2* was similarto Form 2.

Residual acetonitrile and EtOH in Form 2 and 2* was not detected.

TABLE 7 Summary of experiments that generated Forms 2, 2*, and 2** FormSolvent Temperature Wet Dry Form 2 Acetonitrile RT Form 2 Form 2Acetonitrile 50° C. Form 2* Form 2 EtOH/water RT Solvate 3 Form 2 Form2* EtOH RT Form 2* Form 2* EtOH 50° C. Form 2* Form 2* Acetonitrile 50°C. Form 2* Form 2 Form 2** n-Propanol/water RT Form 2** Form 2** *Amountof water in binary solvents is 5%

TABLE 8 XRD peaks of Form 2 2-Theta d(A) BG Height I % Area I % FWHM7.021 12.5802 164 2202 54.1 36151 38.2 0.279 8.298 10.6462 156 194 4.82332 2.5 0.204 10.399 8.5 193 397 9.8 6246 6.6 0.267 11.258 7.8531 206151 3.7 1407 1.5 0.158 12.239 7.2259 181 287 7 5980 6.3 0.354 14.16.2759 186 648 15.9 14147 15 0.371 14.597 6.0632 195 182 4.5 7983 8.40.746 16.18 5.4734 235 201 4.9 4033 4.3 0.341 16.561 5.3484 251 280 6.98382 8.9 0.509 17.033 5.2013 288 160 3.9 1810 1.9 0.192 17.639 5.0238295 366 9 3542 3.7 0.165 18.878 4.6968 316 1210 29.7 29303 31 0.41219.22 4.614 333 585 14.4 21169 22.4 0.615 19.863 4.4662 340 95 2.3 4370.5 0.078 20.411 4.3474 385 86 2.1 671 0.7 0.133 21.48 4.1335 532 194447.8 61345 64.8 0.536 22.04 4.0297 647 4071 100 94605 100 0.395 23.0363.8576 634 142 3.5 1478 1.6 0.177 24.24 3.6686 497 1688 41.5 28976 30.60.292 25.561 3.482 422 120 2.9 2545 2.7 0.361 25.918 3.4349 365 271 6.711426 12.1 0.717 26.379 3.3759 349 497 12.2 15133 16 0.518 26.739 3.3313387 181 4.4 2845 3 0.267 27.979 3.1863 297 235 5.8 4050 4.3 0.293 29.0433.072 338 347 8.5 4584 4.8 0.225 29.661 3.0094 321 310 7.6 7879 8.30.432 30.204 2.9565 355 135 3.3 1501 1.6 0.189 31.58 2.8308 232 206 5.13991 4.2 0.329 32.602 2.7443 193 63 1.5 1129 1.2 0.305

TABLE 9 XRD peaks of Form 2* 2-Theta d(A) BG Height I % Area I % FWHM4.859 18.1701 127 87 1.2 1714 1.9 0.335 7.119 12.4067 148 3587 48.444853 50.4 0.213 8.321 10.6166 149 407 5.5 4871 5.5 0.203 10.439 8.4669186 1184 16 13629 15.3 0.196 11.319 7.8109 190 413 5.6 4673 5.3 0.19212.3 7.1899 179 1010 13.6 13220 14.9 0.223 12.803 6.9089 182 140 1.91587 1.8 0.193 14.121 6.2667 179 1966 26.5 27290 30.7 0.236 14.5596.0791 199 169 2.3 4381 4.9 0.441 16.236 5.4546 244 436 5.9 5696 6.40.222 16.62 5.3297 271 674 9.1 7919 8.9 0.2 17.059 5.1935 313 629 8.56279 7.1 0.17 17.699 5.0071 303 1094 14.7 12619 14.2 0.196 18.858 4.7018359 2334 31.5 31734 35.7 0.231 19.321 4.5903 325 1650 22.2 28313 31.80.292 19.823 4.4751 412 127 1.7 582 0.7 0.078 20.321 4.3665 327 333 4.53361 3.8 0.172 21.479 4.1336 451 3245 43.8 56365 63.3 0.295 22.1194.0154 612 7417 100 89000 100 0.204 22.782 3.9 536 327 4.4 11890 13.40.618 23.098 3.8475 466 638 8.6 11127 12.5 0.296 24.3 3.6597 361 487365.7 61170 68.7 0.213 25.599 3.4769 487 475 6.4 7278 8.2 0.26 25.883.4399 541 562 7.6 10968 12.3 0.332 26.361 3.3782 372 1289 17.4 2085923.4 0.275 26.739 3.3312 266 660 8.9 13196 14.8 0.34 27.938 3.1909 284560 7.6 9888 11.1 0.3 28.641 3.1142 319 210 2.8 2324 2.6 0.188 29.3983.0357 357 100 1.3 2376 2.7 0.404 29.779 2.9977 295 708 9.5 13168 14.80.316 30.3 2.9473 283 451 6.1 6600 7.4 0.249 31.658 2.8239 239 667 99228 10.4 0.235 32.519 2.7511 221 191 2.6 2896 3.3 0.258 33.903 2.6419213 72 1 876 1 0.207 34.82 2.5744 229 110 1.5 3822 4.3 0.591 35.5042.5264 230 97 1.3 3876 4.4 0.679

D. Form 3

The experiments that generated Form 3 are shown in Table 10, below. XRDand DSC scans of Form 3 were taken (FIGS. 3A and 3B, respectively).Table 11, below, shows the XRD peaks of Form 3. Multiple exotherms andendotherms were observed from the DSC scan of Form 3.

A TGA scan of Form 3 was taken (FIG. 3C) and showed a 1.6% weight lossof the solid before 81° C., followed by a 1.7% weight loss between 81°C. and 169° C.

Form 3 was obtained from IPAc at RT, while Form 3* was obtained fromreslurry in n-butyl acetate.

TABLE 10 Summary of experiments that generated Form 3 and Form 3* FormSolvent Temperature Wet Dry Form 3 IPAc RT Form 3 Form 3 n-Butyl acetateRT Form 3* Form 3 Form 3* n-Butyl acetate RT Form 3* Form 3

TABLE 11 XRD peaks of Form 3 2-Theta d(A) BG Height I % Area I % FWHM5.024 17.5739 231 87 4.4 845 1.9 0.165 6.34 13.9294 368 1030 52.5 1236127.5 0.204 7.219 12.2357 182 1962 100 36491 81.1 0.316 8.441 10.4665 188159 8.1 3261 7.2 0.349 9.237 9.5659 207 320 16.3 3365 7.5 0.179 10.5618.37 240 278 14.2 6270 13.9 0.383 10.998 8.0381 217 849 43.3 17119 38.10.343 11.46 7.715 256 87 4.4 662 1.5 0.129 12.439 7.11 215 311 15.9 650214.5 0.355 12.865 6.8756 209 92 4.7 1599 3.6 0.295 14.22 6.2233 231 52226.6 12265 27.3 0.399 15.524 5.7034 273 311 15.9 2957 6.6 0.162 16.0215.5276 309 218 11.1 2669 5.9 0.208 16.78 5.2792 368 330 16.8 3780 8.40.195 17.181 5.1567 384 99 5 2614 5.8 0.449 17.782 4.9837 428 496 25.36264 13.9 0.215 18.381 4.8227 509 551 28.1 5102 11.3 0.157 19.02 4.6622447 589 30 20513 45.6 0.592 19.758 4.4896 487 423 21.6 14362 31.9 0.57720.8 4.267 520 214 10.9 1518 3.4 0.121 21.19 4.1893 408 418 21.3 458110.2 0.186 21.6 4.1107 553 1017 51.8 41986 93.3 0.702 22.181 4.0044 6621736 88.5 44981 100 0.44 23.185 3.8333 508 259 13.2 3327 7.4 0.218 24.443.6392 467 1441 73.4 29510 65.6 0.348 25.198 3.5313 551 232 11.8 1362 30.1 25.618 3.4745 557 79 4 365 0.8 0.079 26.103 3.4109 512 180 9.2 737416.4 0.696 26.479 3.3634 475 306 15.6 11652 25.9 0.647 27.3 3.264 455133 6.8 1016 2.3 0.13 28.04 3.1796 378 93 4.7 1485 3.3 0.271 28.823.0953 372 201 10.2 3455 7.7 0.292 29.258 3.0499 362 76 3.9 2580 5.70.577 29.88 2.9878 334 191 9.7 4011 8.9 0.357 31.802 2.8115 251 205 10.44094 9.1 0.34 32.62 2.7429 231 87 4.4 1109 2.5 0.217 32.943 2.7167 21552 2.7 1107 2.5 0.362 33.961 2.6375 217 101 5.1 1686 3.7 0.284

E. Form 4

The experiments that generated Forms 4, 4*, and 4** are shown in Table12, below. XRD of Forms 4, 4*, and 4** were taken (FIGS. 4A, 4D, and 4G,respectively). Tables 13 and 14, below, show the XRD peaks of Form 4 andForm 4*, respectively. DSC scans of Forms 4, 4*, and 4** were alsoperformed (FIGS. 4B, 4E, and 4H, respectively). According to the DSCscans, Form 4 showed a wide endotherm between 50° C.-100° C., followedby multiple endotherms/exotherms, and then melted at around 367° C.Forms 4* and 4** showed similar DSC patterns as Form 4.

TGA scans of Form 4, Form 4*, and Form 4** were taken (FIGS. 4C, 4F, and4I, respectively). For Form 4, there was an 8.3% weight loss before 200°C.; for Form 4*, there was a 4.4% weight loss before 102° C., followedby a 0.5% weight loss between 102° C. and 250° C.; and for Form 4**,there were three stages of weight loss, which were 2.8%, 1.9%, and 1.3%,respectively.

These solid forms were obtained from methyl acetate, n-propanol, MIBK,MtBE, ethyl acetate, acetone/water, and ethyl acetate/water.

TABLE 12 Summary of experiments that generated Forms 4, 4*, and 4** FormSolvent Temperature Wet Dry Form 4 EA RT Form 4* Form 4 EA 50° C. Form4* Form 4 MA RT Form 4 Form 4 MA 50° C. Form 4 Form 4 MA/water 50° C.Form 12 Form 4 MtBE 50° C. Form 5* Form 4 n-Propanol RT Form 4 Form 4*Form 4* EA RT Form 4* Form 4* EA 50° C. Form 4* Form 4 EA/water 50° C.Form 4* Form 4* n-Propanol RT Form 4 Form 4* Form 4** Acetone/water RTSolvate 2 Form 4** Acetone 50° C. Solvate 2 Form 4** n-Propanol 50° C.Form 4 Form 4** Acetone/water 50° C. Form 4** Form 4** *Amount of waterin binary solvents is 5%

TABLE 13 XRD peaks of Form 4 2-Theta d(A) BG Height I % Area I % FWHM3.433 25.7129 197 48 1 697 0.7 0.247 7.019 12.5829 222 3897 77.3 6696869.4 0.292 8.659 10.203 242 448 8.9 8198 8.5 0.311 8.98 9.8395 223 2194.3 7649 7.9 0.594 9.64 9.1672 251 516 10.2 6969 7.2 0.23 10.917 8.0978210 77 1.5 1041 1.1 0.23 12.339 7.1673 220 465 9.2 9572 9.9 0.35 13.826.4023 268 501 9.9 11493 11.9 0.39 14.278 6.1981 271 192 3.8 7288 7.60.645 14.923 5.9314 288 172 3.4 1636 1.7 0.162 16.462 5.3804 310 329 6.53066 3.2 0.158 17.041 5.199 375 105 2.1 942 1 0.153 17.638 5.0241 4351073 21.3 13511 14 0.214 18.281 4.8488 487 772 15.3 9782 10.1 0.21519.52 4.5437 504 1590 31.5 31949 33.1 0.342 21.759 4.081 677 5040 10096504 100 0.326 23.22 3.8275 693 1457 28.9 28109 29.1 0.328 25.12 3.5421710 3091 61.3 69330 71.8 0.381 25.76 3.4556 455 827 16.4 22029 22.80.453 27.221 3.2733 419 180 3.6 2915 3 0.275 28.638 3.1145 409 210 4.24338 4.5 0.351 29.259 3.0498 461 568 11.3 11998 12.4 0.359 30.137 2.9629409 149 3 1946 2 0.222 31.817 2.8102 253 110 2.2 4034 4.2 0.623 32.3192.7677 245 137 2.7 3829 4 0.475

TABLE 14 XRD peaks of Form 4* 2-Theta d(A) BG Height I % Area I % FWHM4.981 17.7282 270 684 15.8 12231 12.6 0.304 7.22 12.2329 244 3416 7965744 67.8 0.327 8.459 10.4447 202 335 7.7 4814 5 0.244 10.56 8.3707 219629 14.5 10739 11.1 0.29 11.42 7.7419 240 203 4.7 2908 3 0.244 12.427.1209 221 614 14.2 11445 11.8 0.317 13.019 6.7947 238 59 1.4 423 0.40.122 14.26 6.2057 227 1052 24.3 20787 21.4 0.336 16.318 5.4274 409 85 2665 0.7 0.133 16.722 5.2973 332 496 11.5 8980 9.3 0.308 17.199 5.1515393 226 5.2 3448 3.6 0.259 17.82 4.9733 402 725 16.8 8502 8.8 0.19918.98 4.672 432 1352 31.3 36895 38.1 0.464 19.44 4.5623 439 990 22.928546 29.4 0.49 20.46 4.3371 444 119 2.8 1163 1.2 0.166 21.58 4.1144 4581982 45.8 71568 73.8 0.614 22.22 3.9974 837 4325 100 96937 100 0.38123.16 3.8373 758 114 2.6 1085 1.1 0.162 24.42 3.6421 522 2466 57 4897750.5 0.338 25.679 3.4663 590 252 5.8 5211 5.4 0.352 26.5 3.3607 470 67115.5 23177 23.9 0.587 26.95 3.3056 356 313 7.2 3645 3.8 0.198 28.1183.1709 385 255 5.9 5045 5.2 0.336 29.9 2.9858 360 383 8.9 13112 13.50.582 30.421 2.9359 346 239 5.5 5602 5.8 0.398 31.779 2.8134 293 336 7.85905 6.1 0.299 32.618 2.743 267 124 2.9 1934 2 0.265

F. Forms 5 and 5*

The experiments that generated Forms 5 and 5* are shown in Table 15,below. XRD scans of Forms 5 and 5* were taken (FIGS. 5A and 5D,respectively). The XRD peaks of Form 5 are shown in Table 16, below. ADSC scan of Form 5 was also performed and showed a wide endothermbetween 50° C.-100° C., and multiple endotherms and exotherms beforemelting at 363° C. (FIG. 5B).

A TGA scan of Form 5 solid showed a 3.1% weight loss before 100° C.,followed by a 1.7% weight loss between 100° C. and 250° C. (FIG. 5C).

Forms 5 and 5* were obtained from slurrying Form 12 in MtBE at RT and50° C. Wet solid showed Form 5*, while dry solid indicated Form 5.

TABLE 15 Summary of experiments that generated Forms 5 and 5* FormSolvent Temperature Wet Dry Form 5 MtBE RT Form 5* Form 5 Form 5* MtBERT Form 5* Form 5 MtBE 50° C. Form 5* Form 4

TABLE 16 XRD peaks of Form 5 2-Theta d(A) BG Height I % Area I % FWHM5.098 17.3185 260 155 2.4 2464 2.1 0.27 6.38 13.8428 256 1778 27.7 3473329.6 0.332 7.28 12.1332 214 3964 61.6 78158 66.5 0.335 8.518 10.3715 234241 3.7 3170 2.7 0.224 9.24 9.5627 227 472 7.3 6614 5.6 0.238 10.6398.3083 266 765 11.9 20508 17.5 0.456 11.019 8.0226 242 1596 24.8 3762032 0.401 11.483 7.6998 398 133 2.1 949 0.8 0.121 12.44 7.1091 246 5849.1 11910 10.1 0.347 12.94 6.8358 249 152 2.4 4189 3.6 0.469 14.3016.1883 279 1114 17.3 22226 18.9 0.339 14.839 5.9648 300 167 2.6 5989 5.10.61 15.581 5.6827 404 376 5.8 4045 3.4 0.183 16.08 5.5073 452 459 7.19013 7.7 0.334 16.357 5.4146 509 260 4 11967 10.2 0.782 16.839 5.2606521 473 7.4 7195 6.1 0.259 17.254 5.1351 550 258 4 4373 3.7 0.288 17.8394.968 562 414 6.4 4207 3.6 0.173 18.439 4.8078 667 590 9.2 5946 5.10.171 19.059 4.6527 616 1603 24.9 35964 30.6 0.381 19.5 4.5486 671 116318.1 30384 25.9 0.444 20.882 4.2506 850 305 4.7 2860 2.4 0.159 21.6794.0959 935 2272 35.3 66194 56.4 0.495 22.28 3.9867 1083 6430 100 117449100 0.311 23.221 3.8273 856 564 8.8 9429 8 0.284 24.461 3.6361 697 425066.1 74709 63.6 0.299 25.276 3.5206 726 170 2.6 1349 1.1 0.135 26.0813.4137 756 442 6.9 17518 14.9 0.674 26.52 3.3582 689 1014 15.8 3461529.5 0.58 28.139 3.1686 528 306 4.8 4846 4.1 0.269 28.821 3.0952 533 4637.2 7067 6 0.259 29.94 2.9819 499 755 11.7 15565 13.3 0.35 30.458 2.9324435 467 7.3 9861 8.4 0.359 31.86 2.8065 343 648 10.1 13697 11.7 0.35932.642 2.741 314 125 1.9 2403 2 0.327 34.002 2.6344 298 123 1.9 1956 1.70.27

G. Form 6

The experiments that generated Form 6 are shown in Table 17, below. XRDand DSC scans of Form 6 were taken (FIGS. 6A and 6B, respectively).According to the DSC scan, the solid showed a small exotherm at 250° C.and a sharp melting endotherm at 358° C.

Form 6 was obtained by slurrying starting material in IPA and IPA/5%water at RT and 50° C.

TABLE 17 Summary of experiments that generated Form 6 Form SolventTemperature Wet Dry Form 6 IPA RT Form 6 Form 6 IPA 50° C. Form 6 Form 6IPA/water RT Form 6 Form 6 IPA/water 50° C. Form 6 Form 6 *Amount ofwater in binary solvents is 5%

H. Form 7

The experiments that generated Form 7 are shown in Table 18, below. XRDand DSC scans of Form 7 were taken (FIGS. 7A and 7B, respectively). TheXRD peaks of Form 7 are shown in Table 19, below. According to the DSCscan, the solid showed two exotherms at 227° C. and 299° C., followed bya melting endotherm at 365° C. Form 7 showed low degree of crystallinityon XRD. The double exotherm on the DSC scans may be associated with thelow crystallinity observed on the XRD scan.

A TGA scan of Form 7 solid showed a 12% weight loss before 200° C. (FIG.7C).

Form 7 was obtained from MEK and MEK/5% water at RT and 50° C.

TABLE 18 Summary of experiments that generated Form 7 Form SolventTemperature Wet Dry Form 7 MEK RT Form 7 Form 7 MEK 50° C. Form 7 Form 7MEK/water RT Form 7 Form 7 MEK/water 50° C. Form 7 Form 7 *Amount ofwater in binary solvents is 5%

TABLE 19 XRD peaks of Form 7 2-Theta d(A) BG Height I % Area I % FWHM4.94 17.8745 362 1384 23.3 50829 29.2 0.624 7.06 12.5111 286 3171 53.369159 39.8 0.371 8.759 10.0876 370 628 10.6 9606 5.5 0.26 9.9 8.9272 429537 9 11110 6.4 0.352 10.881 8.1241 546 879 14.8 16425 9.4 0.318 11.847.4681 588 413 6.9 7187 4.1 0.296 12.997 6.8061 463 135 2.3 1351 0.80.17 14.404 6.1442 604 126 2.1 3331 1.9 0.449 15.1 5.8626 791 596 108819 5.1 0.252 15.92 5.5622 792 593 10 24460 14.1 0.701 16.581 5.3421739 641 10.8 14919 8.6 0.396 18.5 4.7919 1066 1555 26.1 43174 24.8 0.47219.4 4.5717 1087 930 15.6 17521 10.1 0.32 20.382 4.3535 1178 154 2.6 8670.5 0.096 21.56 4.1183 1424 5949 100 173972 100 0.497 22.098 4.0192 1830692 11.6 17678 10.2 0.434 23.22 3.8275 1749 1971 33.1 42151 24.2 0.36424.203 3.6743 1776 351 5.9 11935 6.9 0.578 24.884 3.5751 1658 271 4.62378 1.4 0.149 25.759 3.4556 1416 492 8.3 19894 11.4 0.687 26.3 3.38581335 499 8.4 23631 13.6 0.805 27.34 3.2594 1192 307 5.2 4494 2.6 0.24928.641 3.1142 1004 382 6.4 18030 10.4 0.802 29.078 3.0684 979 324 5.414234 8.2 0.747 30.28 2.9492 759 711 12 16004 9.2 0.383 31.985 2.7959551 111 1.9 4816 2.8 0.738 33.402 2.6804 509 102 1.7 2060 1.2 0.34334.24 2.6167 474 92 1.5 1901 1.1 0.351

I. Form 8

The experiments that generated Form 8 are shown in Table 20, below. XRDand DSC scans of Form 8 were taken (FIGS. 8A and 8B, respectively). TheXRD peaks of Form 8 are shown in Table 21, below. According to the DSCscan, the solid showed two endotherms at 205° C. and 231° C., followedby an exotherm at 279° C., followed by a melting endotherm at 362° C.Form 8 showed a low degree of crystallinity on the XRD scan. The doubleexotherm on the DSC scan may confirm the low crystallinity seen on XRD(low crystalline material convert to higher crystallinity solid).

A TGA scan of Form 8 showed a 4.2% weight loss before 190° C., followedby a 3.9% weight loss between 190° C. and 261° C. (FIG. 8C).

Form 8 was obtained from MIBK at RT and 50° C. MIBK/5% water reslurrydoes not produce the same form.

TABLE 20 Summary of experiments that generated Form 8 Form SolventTemperature Wet Dry Form 8 MIBK RT Form 8 Form 8 MIBK 50° C. Form 8 Form8

TABLE 21 XRD peaks of Form 8 2-Theta d(A) BG Height I % Area I % FWHM6.88 12.8368 318 2815 80.8 71578 51.7 0.432 10.699 8.2619 380 70 2 7220.5 0.175 11.48 7.7016 344 466 13.4 9513 6.9 0.347 12.66 6.9866 348 1363.9 1759 1.3 0.22 14.16 6.2496 435 166 4.8 3298 2.4 0.338 15.259 5.8017483 269 7.7 6267 4.5 0.396 16.879 5.2484 669 333 9.6 7638 5.5 0.3917.681 5.0121 780 1959 56.2 76035 54.9 0.66 19.618 4.5213 833 134 3.82110 1.5 0.268 21.5 4.1296 1116 3484 100 138450 100 0.676 24.244 3.6682899 99 2.8 2643 1.9 0.454 27.559 3.234 753 366 10.5 11182 8.1 0.51928.881 3.0889 636 279 8 8137 5.9 0.496 30.878 2.8935 403 87 2.5 1890 1.40.369 31.221 2.8624 386 69 2 1898 1.4 0.468

J. Form 9

The experiments that generated Form 9 are shown in Table 22, below. XRDand DSC scans of Form 9 were taken (FIGS. 9A and 9B, respectively). TheXRD peaks of Form 9 are shown in Table 23, below. According to the DSCscan, the solid showed a single melting endotherm at 364° C.

A TGA scan of Form 9 showed a 0.28% weight loss before 100° C. (FIG.9C).

Other forms, when heated to just before melting at 364° C., seemed toconvert to Form 9. This has been confirmed for Forms 1 and 2.

A DVS scan of Form 9 showed a 0.8% water absorption at 90% RH. Form 9did not change its form before and after the DVS scan (FIG. 9D).

TABLE 22 Summary of experiments that generated Form 9 Form SolventTemperature Wet Dry n-Butanol RT Form 9 Form 9 Form 9 IPAc 50° C. Form 9Form 9 n-Butyl acetate 50° C. Form 9 Form 9 n-Butanol 50° C. Form 9 Form9 EtOH/water 50° C. Form 9 Form 9 n-Propanol/water 50° C. Form 9 Form 9*Amount of water in binary solvents is 5%

TABLE 23 XRD peaks of Form 9 2-Theta d(A) BG Height I % Area I % FWHM4.94 17.8746 21 895 100 23398 100 0.444 6.26 14.1076 21 34 3.8 513 2.20.257 10.099 8.7516 28 66 7.4 1172 5 0.302 11.883 7.4413 30 46 5.1 8283.5 0.306 13.16 6.7221 27 37 4.1 400 1.7 0.184 15.341 5.771 39 71 7.91541 6.6 0.369 16.518 5.3622 40 93 10.4 1728 7.4 0.316 18.622 4.7608 46260 29.1 7069 30.2 0.462 19.74 4.4938 80 138 15.4 1937 8.3 0.239 21.1014.2068 64 342 38.2 8314 35.5 0.413 22.42 3.9622 56 77 8.6 1721 7.4 0.3824.1 3.6897 58 198 22.1 3904 16.7 0.335 25.2 3.5311 63 157 17.5 361515.5 0.391 26.897 3.312 46 44 4.9 1307 5.6 0.505 28.577 3.121 35 54 61754 7.5 0.552 29.884 2.9874 32 30 3.4 477 2 0.254 30.926 2.8891 35 323.6 682 2.9 0.341

K. Forms 10 and 10*

The experiments that generated Forms 10 and 10* are shown in Table 24,below. XRD scans of Forms 10 and 10* were taken (FIGS. 10A and 10D,respectively). The XRD peaks of Form 10 are shown in Table 25, below.DSC scans of Forms 10 and 10* were also taken and indicated multipleendotherms/exotherms, followed by melting at 367° C. (FIGS. 10B and 10E,respectively).

Forms 10 and 10* were produced by drying of amorphous solids (obtainedfrom DMSO and DMSO/water reslurry at RT and 50° C.). Both Form 10 and10* are associated with DMSO.

A TGA scan of Form 10 solid showed a 0.6% weight loss before 100° C.,followed by a 3.8% weight loss between 100° C. and 170° C., followed bya 7.1% weight loss between 170° C. and 260° C. (FIG. 10C).

TABLE 24 Summary of experiments that generated Forms 10 and 10* FormSolvent Temperature Wet Dry Form 10 DMSO RT amorphous Form 10 DMSO/waterRT amorphous Form 10 DMSO/water 50° C. amorphous Form 10 Form 10* DMSO50° C. amorphous Form 10* *Amount of water in binary solvents is 5%

TABLE 25 XRD peaks of Form 10 2-Theta d(A) BG Height I % Area I % FWHM6.701 13.1792 148 1553 32.1 31364 34.4 0.343 8.3 10.6444 207 1026 21.217914 19.6 0.297 9.38 9.4203 212 1352 27.9 21528 23.6 0.271 10.8198.1705 223 514 10.6 8714 9.6 0.288 11.919 7.4192 271 635 13.1 9435 10.30.253 12.919 6.8469 266 1160 24 22094 24.2 0.324 13.718 6.45 242 81 1.7856 0.9 0.18 14.84 5.9646 271 244 5 4716 5.2 0.329 15.536 5.6988 312 1473 1304 1.4 0.151 16.58 5.3424 392 1813 37.5 30451 33.4 0.286 17.8214.9731 434 2208 45.6 58342 64 0.449 18.16 4.881 434 2862 59.2 89029 97.60.529 19.001 4.6667 1021 3215 66.5 45840 50.2 0.242 19.88 4.4623 11631454 30.1 19014 20.8 0.222 20.701 4.2873 1514 4838 100 78140 85.7 0.27521.66 4.0994 596 4067 84.1 91229 100 0.381 23.38 3.8017 596 2251 46.564928 71.2 0.49 24.22 3.6717 663 4578 94.6 84228 92.3 0.313 26 3.4242595 430 8.9 11172 12.2 0.442 27.12 3.2853 639 146 3 1986 2.2 0.231 27.883.1974 642 2073 42.8 48132 52.8 0.395 28.88 3.089 638 477 9.9 14155 15.50.504 29.867 2.9891 544 205 4.2 4572 5 0.379 30.32 2.9454 528 568 11.711936 13.1 0.357 31.098 2.8735 517 443 9.2 5841 6.4 0.224 31.661 2.8236433 118 2.4 953 1 0.137 33.379 2.6822 433 311 6.4 9235 10.1 0.505 34.222.6181 444 281 5.8 6059 6.6 0.367 34.822 2.5743 460 84 1.7 2707 3 0.54835.438 2.5309 465 89 1.8 858 0.9 0.164

L. Forms 11 and 11*

The experiments that generated Forms 11 and 11* are shown in Table 26,below. XRD scans of Forms 11 and 11* were taken (FIGS. 11A and 11D,respectively). The XRD peaks of Form 11 and Form 11* are shown in Tables27 and 28, below, respectively. DSC scans of Forms 11 and 11* were alsotaken (FIGS. 11B and 11E, respectively). According to the DSC scans, thesolid showed multiple endotherms/exotherms and eventually melted at 368°C. Amorphous halo was observed in the XRD of both Forms. The doubleexotherm on the DSC of both forms may be also associated with theamorphous halo observed on XRD scans.

TGA scans of Form 11 and 11* were taken (FIGS. 11C and 11F,respectively). Form 11 solids showed a 0.8% weight loss before 100° C.,followed by a 7.0% weight loss between 100° C. and 249° C. Form 11*solids showed a 1.0% weight loss before 100° C., and followed by a 7.0%weight loss before 250° C.

Forms 11 and 11* were obtained from DMF and DMF/5% water at RT and 50°C.

TABLE 26 Summary of experiments that generated Forms 11 and 11* FormSolvent Temperature Wet Dry Form 11 DMF RT Form 11 Form 11 DMF 50° C.Form 11 Form 11* DMF/water RT Form 11 Form 11 DMF/water 50° C. Form 11Form 11 Form 11* DMF 50° C. Form 11 Form 11* *Amount of water in binarysolvents is 5%

TABLE 27 XRD peaks of Form 11 2-Theta d(A) BG Height I % Area I % FWHM6.42 13.7554 19 496 81.7 9502 100 0.326 8.421 10.4908 20 335 55.2 577560.8 0.293 8.86 9.9726 24 166 27.3 4268 44.9 0.437 10.859 8.1404 21 9115 1292 13.6 0.241 12.479 7.0871 44 83 13.7 1004 10.6 0.206 12.9776.8165 29 51 8.4 1542 16.2 0.514 14.519 6.0957 28 91 15 1421 15 0.26516.801 5.2727 57 104 17.1 2226 23.4 0.364 17.801 4.9787 103 358 59 510953.8 0.243 18.519 4.7871 101 607 100 8460 89 0.237 18.861 4.7011 102 12520.6 1763 18.6 0.24 19.922 4.453 85 383 63.1 7376 77.6 0.327 20.258 4.3879 180 29.7 5778 60.8 0.546 20.899 4.247 76 105 17.3 1291 13.6 0.20921.738 4.085 86 55 9.1 757 8 0.234 22.441 3.9585 94 471 77.6 7125 750.257 22.859 3.8871 78 167 27.5 3724 39.2 0.379 24.458 3.6365 60 29849.1 4544 47.8 0.259 26.82 3.3213 45 195 32.1 4777 50.3 0.416 29 3.076443 99 16.3 3112 32.8 0.534 29.524 3.023 63 37 6.1 190 2 0.087 31.042.8788 38 46 7.6 826 8.7 0.305 31.825 2.8095 36 56 9.2 737 7.8 0.22432.456 2.7563 31 40 6.6 857 9 0.364

TABLE 28 XRD peaks of Form 11* 2-Theta d(A) BG Height I % Area I % FWHM6.441 13.7116 24 424 93.4 8643 100 0.347 6.944 12.7196 20 84 18.5 207824 0.421 8.518 10.3718 22 227 50 4871 56.4 0.365 8.86 9.9721 23 147 32.43581 41.4 0.414 10.859 8.141 26 107 23.6 1695 19.6 0.269 12.519 7.064834 90 19.8 2165 25 0.409 13.021 6.7935 31 54 11.9 1517 17.6 0.478 14.6186.0547 32 76 16.7 1605 18.6 0.359 16.638 5.3238 55 115 25.3 2410 27.90.356 17.838 4.9684 71 368 81.1 6709 77.6 0.31 18.522 4.7864 130 454 1007473 86.5 0.28 19.96 4.4447 109 315 69.4 6433 74.4 0.347 20.26 4.3795109 146 32.2 5359 62 0.624 20.904 4.2461 127 58 12.8 559 6.5 0.16421.639 4.1034 142 194 42.7 4690 54.3 0.411 22.441 3.9586 161 368 81.15409 62.6 0.25 22.94 3.8735 78 150 33 6057 70.1 0.686 23.398 3.7988 78116 25.6 2330 27 0.341 24.44 3.6391 75 305 67.2 5097 59 0.284 26.8193.3215 68 206 45.4 4795 55.5 0.396 29.018 3.0745 56 109 24 4093 47.40.638 29.566 3.0188 82 43 9.5 341 3.9 0.135 31.022 2.8804 58 55 12.1 5095.9 0.157 31.881 2.8047 49 48 10.6 482 5.6 0.171 32.338 2.7661 42 50 111360 15.7 0.462

M. Form 13 and Form 12

The experiments that generated Form 13 and Form 12 are shown in Tables29 and 31, below, respectively. Forms 12 and 13 are examples ofnon-stoichiometric hydrates of Form 1 that have between 1% and about 20%by weight water. XRD scans of Form 13 and Form 12 were taken (FIGS. 13Aand 12A, respectively). The XRD peaks of Form 13 are shown in Table 30,below. DSC scans of Form 13 and Form 12 were also taken (FIGS. 13B and12B, respectively). According to the DSC scan, Form 13 solids showed awide endotherm between 50° C.-100° C., followed by a small exotherm at278° C.; and a melting endotherm at 363° C. According to the DSC scan,Form 12 solids showed a wide endotherm between 50° C.-100° C., followedby a sharp exotherm at 283° C.; and a melting endotherm at 364° C.

The purity of the Form 13 sample was 98.8%; the KF of an undried Form 13sample was 35.7%. A DVS scan of Form 13 solid showed a 17% watersorption at 90% RH (FIG. 13D). Form 13 converted to Form 1 upon drying.

A TGA scan of Form 13 solid showed a 1.9% weight loss before 100° C.(FIG. 13C).

Form 13 solid was heated in a DSC chamber to 170° C. (past the endothermbetween 50-100° C.), and then scanned by XRD. A comparison of the firstand the second XRD and DSC scans, after heating to 170° C., showed thatForm 13 converted to Form 1. It can be concluded that the endothermbetween 50-100° C. is due to bonded water.

Form 13 solid was heated in a DSC chamber to 330° C. (past theendotherm/exotherm around 300° C.), and then scanned by XRD. Acomparison of the first and the third XRD and DSC scans, after heatingto 170° C., showed that Form 13 converted to Form 9. It can be concludedthat the endotherm/exotherm is due to melting/crystallization events.

TABLE 29 Summary of experiments that generated Form 13 Form SolventTemperature Wet Dry Form 13 MeOH RT Form 13 Form 1 MeOH/water 50° C.Form 13 Form 13 water RT Form 13 Form 1 water 50° C. Form 13 Form 13Toluene/water RT Form 13 Form 1 Toluene/water 50° C. Form 13 Form 13MA/water RT Form 13 Form 1 n-Butyl RT Form 13 Form 12 acetate/watern-Butyl 50° C. Form 13 Form 1 acetate/water Heptane 50° C. Form 13 Form13 Heptane/water RT Form 13 Form 12 Heptane/water 50° C. Form 13 Form 1n-Butanol/water RT Form 13 Form 13 n-Butanol/water 50° C. Form 13 Form 1DCM 50° C. Form 13 Form 13 DCM/water RT Form 13 Form 1 DCM/water 50° C.Form 13 Form 1 Acetonitrile/water 50° C. Form 13 Form 13 IPAc/water 50°C. Form 13 Form 13 MtBE/water 50° C. Form 13 Form 13 MIBK/water 50° C.Form 13 Form 1 *Amount of water in binary solvents is 5%

TABLE 30 XRD peaks of Form 13 2-Theta d(A) BG Height I % Area I % FWHM5.06 17.45 278 309 6.5 3685 4.8 0.203 6.379 13.8451 223 4743 100 76110100 0.273 9.24 9.5632 164 1370 28.9 20018 26.3 0.248 11 8.0364 173 344572.6 51777 68 0.256 12.899 6.8574 195 173 3.6 3114 4.1 0.306 13.4626.572 199 204 4.3 2376 3.1 0.198 14.159 6.2498 202 390 8.2 5424 7.10.236 15.56 5.6901 262 1335 28.1 19295 25.4 0.246 16.059 5.5145 302 100221.1 17561 23.1 0.298 16.841 5.26 313 774 16.3 7797 10.2 0.171 17.465.075 322 314 6.6 3863 5.1 0.209 18.419 4.8128 339 2354 49.6 29374 38.60.212 19.3 4.5951 357 210 4.4 8112 10.7 0.657 19.741 4.4935 329 1566 3330236 39.7 0.328 20.202 4.3919 342 210 4.4 2880 3.8 0.233 20.84 4.2589300 1054 22.2 18033 23.7 0.291 21.201 4.1873 284 964 20.3 15700 20.60.277 22.121 4.015 259 197 4.2 2208 2.9 0.191 23.2 3.8307 268 482 10.27844 10.3 0.277 24.42 3.642 280 1101 23.2 16244 21.3 0.251 24.839 3.5816303 468 9.9 9306 12.2 0.338 25.219 3.5284 385 1093 23 16646 21.9 0.25926.164 3.4032 359 357 7.5 5064 6.7 0.241 26.499 3.3609 402 317 6.7 73169.6 0.392 26.798 3.324 346 179 3.8 8025 10.5 0.762 27.339 3.2594 394 72015.2 13063 17.2 0.308 27.639 3.2247 341 318 6.7 5673 7.5 0.303 28.7993.0974 256 805 17 16756 22 0.354 29.902 2.9857 262 234 4.9 3508 4.60.255 31.234 2.8613 230 106 2.2 1473 1.9 0.236 31.96 2.798 226 308 6.53908 5.1 0.216 32.939 2.717 208 117 2.5 1444 1.9 0.21 33.962 2.6375 199266 5.6 4617 6.1 0.295 34.917 2.5675 217 73 1.5 736 1 0.171

TABLE 31 Summary of experiments that generated Form 12 Form SolventTemperature Wet Dry Form 12 Acetonitrile/water RT Form 12 Form 1MeOH/water RT Form 12 Form 1 IPAc/water RT Form 12 Form 1 EA/water RTForm 12 Form 1 MtBE/water RT Form 12 Form 1 MIBK/water RT Form 12 Form 1n-Butyl RT Form 13 Form 12 acetate/water Heptane/water RT Form 13 Form12 MA/water 50° C. Form 12 Form 4 *Amount of water in binary solvents is5%

N. Solvates 1-3

The experiments that generated Solvates 1, 2, and 3 are shown in Table32, below. Solvates 1 and 2 solids were exposed to air overnight, andthen analyzed by XRD. After the analysis, the solids were dried at 50°C. under vacuum, and then analyzed by XRD again.

After exposure to air overnight, Solvate 1 converted to lowcrystallinity; after drying at 50° C., the sample was still lowcrystallinity solid. After exposure to air overnight, the XRD pattern ofSolvate 2 changed a little; after drying at 50° C., the form remainedthe same as the solid exposed to air overnight.

TABLE 32 Summary of experiments that generated solvates 1-3 Form SolventTemperature Wet Dry Solvate 1 Acetone RT Solvate 1 Low crystallinitySolvate 2 Acetone/water RT Solvate 2 Form 4** Acetone 50° C. Solvate 2Form 4** Solvate 3 EtOH/water RT Solvate 3 Form 2 *Amount of water inbinary solvent is 5%

Example 2: Competitive Slurry Experiments Between Polymorph Forms

In order to find out the thermodynamic stability between the differentforms, several competitive slurry experiments were carried out. Form 1,Form 2, Form 2*, Form 3, Form 4, Form 4*, Form 4**, Form 5, Form 7, Form8, Form 9, Form 10, Form 11, Form 11*, and Form 13 (10 mg for each) wasmixed and slurried in 2 mL of solvent at both RT and 50° C. The solidswere slurried for 3-5 days and then analyzed by XRD. According to theanalytical data, Form 2* was the most stable form in a MeOH, EtOH, andacetone system at both RT and 50° C. Form 4 or 4* was most stable in EAat RT and 50° C. Form 13 was most stable in water at RT and 50° C. Table33 shows the XRD scan results from the competitive slurry experiments.

TABLE 33 XRD scan results of competitive slurry experiments Form after 3days; Form after 5 days; Temperature Solvent wet/dry wet/dry RT MeOHForm 2*/Form 2* Form 2*/Form 2* EtOH Form 2*/Form 2* Form 2*/Form 2*Acetone Form 2*/Form 2* Form 2*/Form 2* EA Form 4/Form 4 Form 4/Form 4water Form 13/Form 13 Form 13/Form 1&Form 13 50° C. MeOH Form 2*/Form 2*Form 2*/Form 2* EtOH Form 2*/Form 2* Form 2*/Form 2* Acetone Form2*/Form 2* Form 2*/Form 2* EA Form 4/Form 4 Form 4*/Form 4* water Form13/Form 13 Form 13/Form 13

In order to find out the thermodynamic stability between Form 13 andForm 9, several competitive slurry experiments were carried out. 15 mgof Form 1, Form 9 and Form 13 solid were mixed in 1 mL of toluene, IPAc,and n-butyl acetate, and slurried for 3 days at RT and 50° C.

The residual solid was analyzed by XRD. After a three-day slurry, it wasdifficult to tell which one was more stable between Form 13 and Form 9.The XRD scan results of the experiment is shown in Table 34, below.

TABLE 34 XRD scan results competitive slurry experiments TemperatureSolvent Form after 3 days; wet/dry RT Toluene Form 13/Form 1 IPAc Form9 + Form 13/Form 9 + Form 1 n-Butyl acetate Form 9 + Form 13/Form 9 +Form 1 50° C. Toluene Form 9 + Form 13/Form 9 + Form 1 IPAc Form 9/Form9 n-Butyl acetate Form 9 + Form 13/Form 9 + Form 1

Example 3: Radiolabeled Studies

A. Plasma Concentrations and Terminal Elimination Half-Lives in theBlood

1. Plasma Concentrations Following a Single Intra-Articular (IA)Injection of Radiolabeled Compound 10 in Rats

Plasma concentration and distribution of Compound 10 following a singleIA injection in Sprague Dawley (SD) rats were investigated inradiolabeled and mass balance studies with a tritium-labeled (³H)Compound 10. [³H]-Compound 10 was formulated as a suspension in 0.5%carboxymethylcellulose/0.05% polysorbate 80 for intra-articular (IA)injection and diluted with unlabeled Compound 10 to the appropriateconcentration and injected in the rat knee joint at a dose levelequivalent to 1 μg/knee. Following the single IA injection, lowcirculating plasma levels (0.002 to 0.075 ng-equivalents/g) whichdeclined over time (48 to 168 hours) were detected in the rat plasma byquantitative radiochemical analysis (QRA) with 50-fold highersensitivity of 2 μg/g or μg/mL over that of the LCMS method (LLOQ of 0.1ng/mL). Mean radioactivity exposures were low, ranging from 0.832 to1.548 ng-equiv.h/g (AUC_((0-t)) and AUC_((0-inf.))) (males) and 1.040 to1.818 ng-equiv.h/g (AUC_((0-t)) and AUC_((0-inf.))) (females), withT_(max) values of 1 and 4 hours and apparent terminal eliminationhalf-lives in the blood of 57 and 124 hours (in males and females,respectively).

2. Plasma Concentration Following Two Single IA Injections

Two single IA injections of the 1 μg/knee of the suspension describedabove containing Compound 10 radiolabeled with tritium were made in bothknee joints of SD rats. Low circulating plasma radioactivity (0.010 to0.055 ng-equivalents/g) was detected with a dose-proportional increasefollowing two (bilateral) IA injections compared to a single IAinjection (see above) and a clear exponential decline from 48 to 168hours.

B. Quantitative Whole Body Autoradiography and Excretion of RadiolabeledCompound 10 in Rats

1. Quantitative Whole Body Autoradiography in Rats

Following two IA injections at 1 μg/knee in SD rats, quantitative wholebody autoradiography (QWBA) indicated ˜75% total radioactivity wasrecovered from the whole carcass, feces, urine and cage wash, andautoradiographic images indicated that radioactivity was confined in thelymph nodes (inguinal and lumbar lymph nodes that drain the hind legs),small and large intestines, and fecal matter, andnegligible/undetectable in major organs at 1 hour and up to 168 hourspost-IA injection.

2. Excretion of Radiolabeled Compound

In terms of excretion, 95% of the excreted radioactivity was recoveredin the feces and only 5% in the urine. QWBA radiographic images andquantitation of radioactivity in the feces with much less recovery inthe urine, support the hypothesis that [³H]-Compound 10 is beingeliminated by drainage in the lumbar and inguinal lymph ducts and lymphnodes, and through the small and large intestines and cecum in amechanism consistent with slow passive fecal excretion, a major route ofelimination of slowly metabolized xenobiotics. During this process, theradiolabeled [³H]-Compound 10 was degraded with only ˜1.5% of parentdetected in the fecal matter.

C. Persistence of Radiolabeled Compound of Compound 10 in the KneeJoints

1. Rabbit Knee Joints

In rabbits, following two single IA injections in two knees at 4 μg/knee(corresponding to the mid clinical dose of 70 μg/knee), 75% ofadministered radioactivity was recovered in the knee after 1 hour up to168 hours, consistent with the recoveries in the SD rat knee joints.Rabbit knee joint microautoradiography indicated that radioactivity wasconfined in the fluid-filled synovial space and bursa, and surroundedthe meniscus and femoral and tibial bone heads, following IA injection.

2. Rat Knee Joints

Following two IA injections at 1 μg/knee in the SD rats, hind legs wereexcised and solubilized for quantitation of radiolabeled [³H]-Compound10 in the whole knee joint at different time points post-IA injections:1 h, 4 h, 12 h, 24 h, 48 h, 96 h and 168 h. These same animals were usedfor the QWBA experiments (above). Knee joint recoveries indicated that˜60-85% of the administered radioactivity was recovered in each kneejoint immediately 1 h post-IA injection up to 168 h (1 week). Thevariable values obtained at 1 h to 168 h were due to the use of the sameanimals for QWBA and incomplete excision of the knees from the wholeanimal for solubilization, but it is generally consistent with thevalues recovered in the rabbit knee joint above (see above).

Further time points (Days 14-180) were collected from different animalsnot used for QWBA, resulting in more consistent recoveries between thehind legs A and

B. Quantitation of [³H]-Compound 10 in the solubilized knee jointindicated that there was a progressive decrease of [³H]-Compound 10 inthe knee joint, with mean values of 64%, 54%, 42% and 38% ofadministered dose per knee on Days 14, 30, 60 and 90, respectively. OnDay 180, only about ˜6.6% of administered dose was detected.

The stability and radiochemical purity (RCP) of the radiolabeled[³H]-Compound 10 was established in a concurrent experiment where aformulation of radiolabeled [3^(H)]-Compound 10 was incubated at 37° C.and radiochemical purity (RCP) of aliquots were analyzed over time anddetermined to be ˜95.5% (Days 0, 7, 14 and 30), 94.5% (Day 60), 93% (Day90), and 83% (Day 180). Radiographic images were obtained and indicatedthat Compound 10 was still detectable in the knee joint space on Day180.

D. Half-Life in Rat Knee Joints

The half-life (T_(1/2)) of [³H]-Compound 10 in the knee joint of SD ratswas calculated using the radioactivity values recovered in the rat hindlegs (knee joints) on Days 14 to 180: T_(1/2)=51.64 days (including alltime points, Days 14-180) with elimination rate constant, K_(e), of0.01342, and T_(1/2)=100.9 days (time points Days 14-90 only, butexcluding Day 180) with elimination rate constant, K_(e), of 0.00687.

Example 4: Production and Inhibition of Interleukin 6 (IL-6) in HumanMonocyte Cells

Representative compounds of Formula (I) were screened using thefollowing assay procedure to determine their ability to inhibit IL-6 andtherefore demonstrate their anti-inflammatory properties.

Human Monocyte Cell Culture:

A human monocyte cell line (THP-1 cells; Catalog # TIB-202, ATCC,Manassas, Va.) was cultured in Roswell Park Memorial Institute (RPMI)1640 Medium (Catalog #21870-100, Buffalo, N.Y.) with 1% L-glutamine, 1%HEPES, 1% sodium pyruvate, 2% sodium bicarbonate supplemented with 100units/mL penicillin, 50 μg/mL streptomycin, 2-mercaptoethanol (0.05 mM)[basal medium] and 10% fetal bovine serum (Catalog #16140089, LifeTechnologies, Carlsbad, Calif.) at 37° C. and 5% CO₂.

Compound Screening:

THP-1 cells were cultured in basal media with 1% FBS for 24 hours beforethe start of the assay. Each compound of Formula (I) was dissolved inDMSO as a 10 mM stock and used to prepare compound source plates. Serialdilution (1:3, 10-point dose-response curves starting from 10 μM) andcompound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale,Calif.) into 384-well white low volume assay plates (Greiner Bio-One)with appropriate DMSO backfill for a final DMSO concentration of 0.1%.THP-1 cells were plated at 5000 cells/well in the 384-well plates andincubated at 37° C. for 2 h. 500 ng/mL of LPS was added after 2 hoursand cells were incubated for another 22 hours at 37° C. Plates were spunin a centrifuge for 1 minute at 10,000 rpm and a mixture of anti-IL-6XL665, and anti-IL-6 Cryptate diluted in reconstitution buffer (CisbioInc.) was added to each well. Following incubation for 3 hrs at roomtemperature, homogeneous time-resolved fluorescence (HTRF) was measuredusing the Envision (Perkin Elmer) at 665 nm and 620 nM. The ratio offluorescence at 665 nm to 620 nm was used as a readout for IL-6quantification. All samples were processed in duplicate. Readings werenormalized to DMSO treated cells and normalized activities were utilizedfor EC₅₀ calculations using the dose-response log (inhibitor) vs.response-variable slope (four parameters) nonlinear regression featureavailable in GraphPad Prism 5.0 (or Dotmatics). For EC₅₀ of >10 M, thepercent inhibition at 10 μM is provided.

Table 35 shows the activity of representative compounds of Formula (I).

TABLE 35 Compound EC₅₀ (μM) 1 0.451 2 0.290 3 0.273 4 0.074 5 0.349 60.232 7 2.431 9 2.258 10 0.013 11 0.033 12 0.045 15 0.023 16 0.134 200.015 24 0.019 31 0.014 86 0.042 89 0.044 90 0.042 91 0.019 94 0.019 970.122 99 0.040 102 0.053 104 7.235 107 0.075 111 0.050 124 0.047 1270.138 136 0.125 154 0.188 163 >10 (30.0%) 164 0.433 170 4.689 173 >10(11.7%) 174 0.016 177 0.030 186 1.176 199 0.103 202 1.223 205 0.016 2110.311 214 0.059 217 0.014 247 0.474 252 0.750 257 0.097 260 0.295 2630.224 268 >10 (27.6%) 274 >10 (24.1%) 275 >10  (9.9%) 280 0.731 283 >10(50.7%) 286 0.827 289 0.016 291 0.011 293 0.058 295 0.047 301 0.127 3031.012 304 0.040 311 0.216 315 0.207 319 0.078 321 0.697 329 0.058 3305.870 333 0.103 336 0.071 339 0.097 342 0.109 346 0.037 349 0.034 3730.034 397 0.014

Example 5: Inhibition of Inflammatory Cytokines in Synovial Fibroblasts

A. Production of Synovial Fibroblasts

Synovial fibroblasts (SW982 cells; ATCC) were cultured in Leibovitz'sL-15 Medium (ATCC) with 10% FBS at 37° C. and 0% CO₂. 24 hours beforethe start of the assay, media was changed to Leibovitz's L-15 Mediumwith 1% FBS. Compound 10 was dissolved in DMSO as a 10 mM stock and usedto prepare compound source plates. A serial dilution (8-pointdose-response) and compound transfer was performed using the ECHO 550(Labcyte, Sunnyvale, Calif.) into 96-well clear bottom assay plates(Greiner Bio-One) with appropriate DMSO backfill for a final DMSOconcentration of 0.05%. Synovial fibroblasts were plated at 2×10e⁴cells/well and stimulated with IL1β (20 ng/ml) and incubated at 37° C.for 48 hrs. Plates were spun in a centrifuge for 1 minute at 10,000 rpmand supernatants were collected for ELISA.

B. Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α)

Supernatants were diluted 1:1 for the TNFα assay and 1:4 for the IL6assay using the assay medium. ELISA was performed using Human TNF-αELISA MAX™ Deluxe (Catalog #430204, Biolegend, San Diego, Calif.) andHuman IL-6 ELISA MAX™ Deluxe (Catalog #430504, Biolegend, San Diego,Calif.) kits. Briefly, 96-well plates were coated with the appropriatecapture antibody overnight and washed to remove excess antibody.Blocking buffer was added and incubated for 1 hour to preventnon-specific binding. Diluted supernatants were incubated in the coatedplates for 2 hours at room temperature. Following washes to removeunbound proteins, biotinylated detection antibody was added andincubated for 30 mins at room temperature, followed by washes to removeunbound excess antibody. Avidin-HRP was then added and incubated for 30mins at room temperature. Following several washes to remove unboundavidin-HRP, the TMB substrate was added and the plates were read on theCytation 3 plate reader (Biotek Inc., Winooski, Vt.) at an absorbance of450 nm with correction at 570 nm. All samples were processed intriplicate. Inhibition profile and EC50 was calculated using Prism 5(GraphPad Software Inc, La Jolla, Calif., USA). See FIGS. 14A and 14B.

C. Interleukin 1β (IL1β)

Synovial fibroblasts were plated in 6-well plates at 0.5 million cellsper well in Leibovitz's L-15 Medium with 1% FBS. Compound 10 dissolvedin DMSO was added to the wells at different concentrations. Following 2hrs of incubation, at 37° C., cells were stimulated with IL1β (20 ng/ml)and incubated at 37° C. for 24 hrs. Cells were harvested bytrypsinization, pelleted, washed with PBS and Total RNA was isolatedusing RNeasy Mini Kit (Qiagen). cDNA was synthesized using theQuantiTect Reverse Transcription kit (Qiagen). qRT-PCR was performedwith QuantiTect SYBR Green PCR Kit (Qiagen) and gene-specific primers,using CFX384 (Biorad). Transcripts were quantitated by comparative Ctmethod and normalized to endogenous controls, β-actin and GAPDH.Inhibition profile is provided in FIGS. 14A and 14B.

Example 6: Production and Inhibition of Inflammatory Cytokines inPrimary Peripheral Blood Mononuclear Cells

Primary peripheral blood mononuclear cells (PBMCs) freshly isolated fromhealthy human donors were obtained from AllCells Inc. and utilized forassays immediately. Compound 10 was dissolved in DMSO as a 10 mM stockand used to prepare compound source plates. A serial dilution (8-pointdose-response) and compound transfer was performed using the ECHO 550(Labcyte, Sunnyvale, Calif.) into 96-well clear bottom assay plates(Greiner Bio-One) with appropriate DMSO backfill for a final DMSOconcentration of 0.05%. PBMCs were plated at 2×10e⁵ cells/well inRoswell Park Memorial Institute (RPMI) 1640 Medium (Catalog #21870-100,Buffalo, N.Y.) with 1% L-glutamine, 1% HEPES, 1% Sodium Pyruvate, 2%Sodium Bicarbonate supplemented with 100 units/mL penicillin, 50 μg/mLstreptomycin and 1% fetal bovine serum (Catalog #16140089, LifeTechnologies, Carlsbad, Calif.). Following 2 hrs of incubation, 500ng/mL of LPS was added to the wells to induce cytokine production, andcells were incubated further for 20 hours at 37° C. Plates were spun ina centrifuge for 1 minute at 10,000 rpm and supernatants were collectedfor ELISA.

Supernatants were diluted appropriately for ELISA. ELISA was performedusing Human TNF-α ELISA MAX™ Deluxe (Catalog #430204, Biolegend, SanDiego, Calif.) and Human IL-6 ELISA MAX™ Deluxe (Catalog #430504,Biolegend, San Diego, Calif.) kits. Briefly, 96-well plates were coatedwith the appropriate capture antibody overnight and washed to removeexcess antibody. Blocking buffer was added and incubated for 1 hour toprevent non-specific binding. Diluted supernatants were incubated in thecoated plates for 2 hours at room temperature. Following washes toremove unbound proteins, biotinylated detection antibody was added andincubated for 30 mins at room temperature, followed by washes to removeunbound excess antibody. Avidin-HRP was then added and incubated for 30mins at room temperature. Following several washes to remove unboundavidin-HRP, the TMB substrate was added and the plates were read on theCytation 3 plate reader (Biotek Inc., Winooski, Vt.) at an absorbance of450 nm with correction at 570 nm. All samples were processed intriplicate. Inhibition profile and EC50 was calculated using Prism 5(GraphPad Software Inc, La Jolla, Calif., USA). Further, supernatantswere used to measure cytokine levels using the MSD U-plex assay kit(Meso Scale Discovery). Levels of cytokines were calculated usingsoftware form Meso Scale Discovery. Inhibition of TNF-α, IL-1β, IL-2,IL-5, IL-6, IL-8, and IFN-γ is shown in FIG. 15.

What is claimed:
 1. A method of treating a disease or disorderassociated with inflammation in a subject in need thereof, the methodcomprising administering to the subject a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is-heteroarylR³R⁴; R² is selected from the group consisting of H,-heteroarylR⁵, -heterocyclylR⁶ and -arylR⁷; R³ is selected from thegroup consisting of H, -heterocyclylR⁸, —NHC(═O)R⁹, NHSO₂R¹⁰, —NR¹¹R¹²and —(C₁₋₆ alkyl)NR¹¹R¹²; with the proviso that R² and R³ are not bothH; R⁴ is 1-3 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino; each R⁵ is independently1-4 substituents each selected from the group consisting of H, C₁₋₉alkyl, halide, —CF₃, —CN, OR¹³, —C(═O)R¹¹, amino and —(C₁₋₆alkyl)NR¹¹R¹²; each R⁶ is independently 1-5 substituents each selectedfrom the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ andamino; each R⁷ is independently 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, amino,—(C₁₋₆ alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹²; R⁸ is 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino; R⁹ isselected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl; R¹⁰ is selected from thegroup consisting of C₁₋₉ alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷,and -carbocyclylR¹⁴; each R¹¹ is independently selected from C₁₋₆ alkyl;each R¹² is independently selected from the group consisting of H andC₁₋₆ alkyl; each R¹¹ and R¹² are optionally linked to form a five or sixmembered heterocyclyl ring; each R¹³ is independently selected from thegroup consisting of H and C₁₋₆ alkyl; R¹⁴ is 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³ and amino.
 2. The method of claim 1, wherein R¹ is pyridineR³R⁴. 3.The method of claim 2, wherein R¹ is pyridin-3-ylR³R⁴.
 4. The method ofclaim 3, wherein R³ is —(C₁₋₆ alkyl)NR¹¹R¹².
 5. The method of claim 4,wherein R³ is —(C₁₋₂ alkyl)NR¹¹R¹², R¹¹ is —(C₁₋₂ alkyl), R¹² is —(C₁₋₂alkyl), and R⁴ is H.
 6. The method of claim 4, wherein R¹¹ and R¹² areoptionally linked to form a five- or six-membered heterocyclyl ring andR⁴ is H.
 7. The method of claim 6, wherein the five- or six-memberedheterocyclyl ring is substituted with 1-2 fluorines.
 8. The method ofclaim 3, wherein R³ is —NHC(═O)R⁹.
 9. The method of claim 8, wherein R⁴is H and R⁹ is selected from the group consisting of —(C₂₋₅ alkyl),phenyl, -carbocyclyl, and —CH₂carbocyclyl.
 10. The method of claim 9,wherein R⁹ is —(C₂₋₅ alkyl).
 11. The method of claim 3, wherein R³ is—NHSO₂R¹⁰.
 12. The method of claim 11, wherein R⁴ is H and R¹⁰ isselected from the group consisting of —(C₁₋₄ alkyl) and phenyl.
 13. Themethod of claim 3, wherein R³ is -heterocyclylR⁸.
 14. The method ofclaim 13, wherein R⁴ is H and the heterocyclyl is selected from thegroup consisting of morpholine, piperazine and piperidine.
 15. Themethod of claim 3, wherein R³ is H and R⁴ is amino.
 16. The method ofany one of claims 3-15, wherein R² is -heteroarylR⁵.
 17. The method ofany one of claims 3-15, wherein R² is -pyridin-3-ylR⁵.
 18. The method ofany one of claims 3-15, wherein R² is -pyridin-3-ylR⁵ and R⁵ is 1-2fluorine atoms.
 19. The method of any one of claims 3-15, wherein R² isthiopheneR⁵.
 20. The method of any one of claims 3-15, wherein R² is-heterocyclylR⁶.
 21. The method of any one of claims 3-15, wherein R² is-heterocyclylR⁶, and R⁶ is selected from the group consisting of H, Fand —(C₁₋₄ alkyl), and the heterocyclyl is selected from the groupconsisting of morpholine, piperazine and piperidine.
 22. The method ofany one of claims 3-15, wherein R² is -arylR⁷.
 23. The method of claim22, wherein R² is -phenylR⁷ and R⁷ is 1-2 halides.
 24. The method ofclaim 23, wherein R⁷ is fluoro.
 25. The method of claim 22, wherein R²is -phenylR⁷ and R⁷ is two substituents consisting of one fluorine atomand either —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² or —(C₁₋₆ alkyl)NHSO₂R¹¹.
 26. Themethod of claim 1, wherein the compound of Formula (I) is selected fromthe group consisting of

or a pharmaceutically acceptable salt thereof.
 27. The method of claim1, wherein the compound of Formula (I) has a structure selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 28. The method of claim1, wherein the compound of Formula (I) has a structure selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 29. The method of claim1, wherein the compound of Formula (I) has a structure selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 30. The method of claim1, wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.
 31. The method of claim30, wherein the compound of Formula (I) is a polymorph.
 32. The methodof claim 31, wherein the polymorph is Form 1 or a non-stoichiometrichydrate of Form 1 having between 1% to about 20% by weight water. 33.The method of any one of claims 1-32, wherein the disease or disorderassociated with inflammation is selected from the group consisting ofachalasia, acne vulgaris, allergy and allergic responses toenvironmental stimuli such as poison ivy, pollen, insect stings andcertain foods, Alzheimer's disease, amyloidosis, angina, (anginapectoris), ankylosing spondylitis, appendicitis, asthma, atheroscleroticcardiovascular disease (atherosclerosis, ASVD), autoimmune diseases,auto inflammatory diseases, bradycardia (bradyarrhythmia),cancer-related inflammation, cardiac hypertrophy (heart enlargement),celiac disease, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), chronic prostatitis, cirrhosis, colitis, dermatitis(including contact dermatitis and atopic dermatitis), diverticulitis,endothelial cell dysfunction, endotoxic shock (septic shock), fibrosis,glomerulonephritis, hemolytic-uremia, hepatitis, HIV and AIDS,hidradenitis suppurativa, hypersensitivities, hypertension, inflammatorybowel disease, interstitial cystitis, intimal hyperplasia, ischemia,leukocyte defects (including but not limited to Chediak-Higashi syndromeand chronic granulomatous diseases such as tuberculosis, leprosy,sarcoidosis, and silicosis), localized inflammatory disease, lunginflammation, lupus, migraine, myopathies, nephritis, oncologicaldisease (including, but not limited to, epithelial-derived cancers suchas, but not limited to, breast cancer and prostate cancer), orbitalinflammatory disease, pain, pancreatitis, pelvic inflammatory disease,polymyositis, post-infection inflammation, Prinzmetal's angina (variantangina), psoriasis, pulmonary hypertension, Raynaud'sdisease/phenomenon, Reiter's syndrome, renal failure, reperfusioninjury, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma,Sjogren's syndrome, smooth muscle cell tumors and metastasis (includingleiomyoma), smooth muscle spasm, stenosis, stroke, thrombotic disease,toxemia of pregnancy, transplant rejection, ulcers, vasculitis, andvasculopathy.
 34. The method of any one of claims 1-33, wherein thedisease or disorder associated with inflammation is selected from thegroup consisting of poison ivy, Alzheimer's disease, ankylosingspondylitis, autoimmune diseases, auto inflammatory diseases,cancer-related inflammation, chronic obstructive pulmonary disease(COPD), colitis, dermatitis (including contact dermatitis and atopicdermatitis), diabetes, diverticulitis, endotoxic shock (septic shock),fibrosis, hidradenitis suppurativa, inflammatory bowel disease, Crohn'sdisease, intimal hyperplasia, localized inflammatory disease, lupus,morphea, orbital inflammatory disease, Idiopathic Orbital InflammatoryDisease, pelvic inflammatory disease, psoriasis, Raynaud'sdisease/phenomenon, rheumatoid arthritis, osteoarthritis, scleroderma,Sjogren's syndrome, tendinopathy, transplant rejection, ulcers,vasculitis, and vasculopathy.
 35. The method of any one of claims 1-34,wherein administration of the compound of Formula (I) results in thedecrease in the amount of a biomarker linked to inflammation in thesubject.
 36. The method of claim 35, wherein the biomarker is aproinflammatory cytokine.
 37. The method of claim 36, wherein theproinflammatory cytokine is selected from the group consisting of IL-1α,IL-1β, IL-2, IL-4, IL-5, L-6, IL-7, IL-8, IL-10, IL-12/IL23p40, IL-13,L-15, IL-16, IL-17A, IL-17F, IL-21, IL-23, TNFα, TNF-β, IFN-γ, CXCL1,CD38, CD40, CD69, IgG, IP-10, L-17A, MCP-1, PGE2, sIL-2, and sIL-6. 38.A method of decreasing the amount of a biomarker associated with aninflammatory disease or disorder in a subject, the method comprisingadministering to the subject a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is-heteroarylR³R⁴; R² is selected from the group consisting of H,-heteroarylR⁵, -heterocyclylR⁶ and -arylR⁷; R³ is selected from thegroup consisting of H, -heterocyclylR⁸, —NHC(═O)R⁹, NHSO₂R¹⁰, —NR¹¹R¹²and —(C₁₋₆ alkyl)NR¹¹R¹²; with the proviso that R² and R³ are not bothH; R⁴ is 1-3 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino; each R⁵ is independently1-4 substituents each selected from the group consisting of H, C₁₋₉alkyl, halide, —CF₃, —CN, OR¹³, —C(═O)R¹¹, amino and —(C₁₋₆alkyl)NR¹¹R¹²; each R⁶ is independently 1-5 substituents each selectedfrom the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ andamino; each R⁷ is independently 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³, amino,—(C₁₋₆ alkyl)NHSO₂R¹¹, —NR¹²(C₁₋₆ alkyl)NR¹¹R¹² and —(C₁₋₆alkyl)NR¹¹R¹²; R⁸ is 1-5 substituents each selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN, OR¹³ and amino; R⁹ isselected from the group consisting of C₁₋₉ alkyl, -heteroarylR⁵,-heterocyclylR⁶, -arylR⁷ and —CH₂carbocyclyl; R¹⁰ is selected from thegroup consisting of C₁₋₉ alkyl, -heteroarylR⁵, -heterocyclylR⁶, -arylR⁷,and -carbocyclylR¹⁴; each R¹¹ is independently selected from C₁₋₆ alkyl;each R¹² is independently selected from the group consisting of H andC₁₋₆ alkyl; each R¹¹ and R¹² are optionally linked to form a five or sixmembered heterocyclyl ring; each R¹³ is independently selected from thegroup consisting of H and C₁₋₆ alkyl; R¹⁴ is 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —CN,OR¹³ and amino.
 39. The method of claim 38, wherein R¹ is pyridineR³R⁴.40. The method of claim 39, wherein R¹ is pyridin-3-ylR³R⁴.
 41. Themethod of claim 40, wherein R³ is —(C₁₋₆ alkyl)NR¹¹R¹².
 42. The methodof claim 41, wherein R³ is —(C₁₋₂ alkyl)NR¹¹R¹², R¹¹ is —(C₁₋₂ alkyl),R¹² is —(C₁₋₂ alkyl), and R⁴ is H.
 43. The method of claim 41, whereinR¹¹ and R¹² are optionally linked to form a five- or six-memberedheterocyclyl ring and R⁴ is H.
 44. The method of claim 43, wherein thefive- or six-membered heterocyclyl ring is substituted with 1-2fluorines.
 45. The method of claim 40, wherein R³ is —NHC(═O)R⁹.
 46. Themethod of claim 45, wherein R⁴ is H and R⁹ is selected from the groupconsisting of —(C₂₋₅ alkyl), phenyl, -carbocyclyl, and —CH₂carbocyclyl.47. The method of claim 46, wherein R⁹ is —(C₂₋₅ alkyl).
 48. The methodof claim 40, wherein R³ is —NHSO₂R¹⁰.
 49. The method of claim 48,wherein R⁴ is H and R¹⁰ is selected from the group consisting of —(C₁₋₄alkyl) and phenyl.
 50. The method of claim 40, wherein R³ is-heterocyclylR⁸.
 51. The method of claim 50, wherein R⁴ is H and theheterocyclyl is selected from the group consisting of morpholine,piperazine and piperidine.
 52. The method of claim 40, wherein R³ is Hand R⁴ is amino.
 53. The method of any one of claims 40-52, wherein R²is -heteroarylR⁵.
 54. The method of any one of claims 40-52, wherein R²is -pyridin-3-ylR⁵.
 55. The method of any one of claims 40-52, whereinR² is -pyridin-3-ylR⁵ and R⁵ is 1-2 fluorine atoms.
 56. The method ofany one of claims 40-52, wherein R² is thiopheneR⁵.
 57. The method ofany one of claims 40-52, wherein R² is -heterocyclylR⁶.
 58. The methodof any one of claims 40-52, wherein R² is -heterocyclylR⁶, and R⁶ isselected from the group consisting of H, F and —(C₁₋₄ alkyl), and theheterocyclyl is selected from the group consisting of morpholine,piperazine and piperidine.
 59. The method of any one of claims 40-52,wherein R² is -arylR⁷.
 60. The method of claim 59, wherein R² is-phenylR⁷ and R⁷ is 1-2 halides.
 61. The method of claim 60, wherein R⁷is fluoro.
 62. The method of claim 59, wherein R² is -phenylR⁷ and R⁷ istwo substituents consisting of one fluorine atom and either —NR¹²(C₁₋₆alkyl)NR¹¹R¹² or —(C₁₋₆ alkyl)NHSO₂R¹¹.
 63. The method of claim 38,wherein the compound of Formula (I) has a structure selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 64. The method of claim38, wherein the compound of Formula (I) is a

or a pharmaceutically acceptable salt thereof.
 65. The method of claim64, wherein the compound of Formula (I) is a polymorph.
 66. The methodof claim 65, wherein the polymorph is Form 1 or hydrated Form I.
 67. Themethod of any one of claims 38-66, wherein the biomarker is aproinflammatory cytokine.
 68. The method of claim 67, wherein theproinflammatory cytokine is selected from the group consisting of IL-1α,IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL23p40, IL-13,IL-15, IL-16, IL-17A, IL-17F, IL-21, IL-23, TNFα, TNF-β, IFN-γ, CXCL1,CD38, CD40, CD69, IgG, IP-10, L-17A, MCP-1, PGE2, sIL-2, and sIL-6. 69.The method of any one of claims 38-68, wherein the amount of thebiomarker is decreased in the subject by an amount of between about 10%and about 100%.
 70. The method of any one of claims 38-69, wherein theinflammatory disease or disorder is selected from the group consistingof achalasia, acne vulgaris, allergy and allergic responses toenvironmental stimuli such as poison ivy, pollen, insect stings andcertain foods, Alzheimer's disease, amyloidosis, angina, (anginapectoris), ankylosing spondylitis, appendicitis, asthma, atheroscleroticcardiovascular disease (atherosclerosis, ASVD), autoimmune diseases,auto inflammatory diseases, bradycardia (bradyarrhythmia),cancer-related inflammation, cardiac hypertrophy (heart enlargement),celiac disease, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), chronic prostatitis, cirrhosis, colitis, dermatitis(including contact dermatitis and atopic dermatitis), diverticulitis,endothelial cell dysfunction, endotoxic shock (septic shock), fibrosis,glomerulonephritis, hemolytic-uremia, hepatitis, HIV and AIDS,hidradenitis suppurativa, hypersensitivities, hypertension, inflammatorybowel disease, interstitial cystitis, intimal hyperplasia, ischemia,leukocyte defects (including but not limited to Chediak-Higashi syndromeand chronic granulomatous diseases such as tuberculosis, leprosy,sarcoidosis, and silicosis), localized inflammatory disease, lunginflammation, lupus, migraine, myopathies, nephritis, oncologicaldisease (including, but not limited to, epithelial-derived cancers suchas, but not limited to, breast cancer and prostate cancer), orbitalinflammatory disease, pain, pancreatitis, pelvic inflammatory disease,polymyositis, post-infection inflammation, Prinzmetal's angina (variantangina), psoriasis, pulmonary hypertension, Raynaud'sdisease/phenomenon, Reiter's syndrome, renal failure, reperfusioninjury, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma,Sjogren's syndrome, smooth muscle cell tumors and metastasis (includingleiomyoma), smooth muscle spasm, stenosis, stroke, thrombotic disease,toxemia of pregnancy, transplant rejection, ulcers, vasculitis, andvasculopathy.
 71. The method of any one of claims 38-70, wherein theinflammatory disease or disorder is selected from the group consistingof poison ivy, Alzheimer's disease, ankylosing spondylitis, autoimmunediseases, auto inflammatory diseases, cancer-related inflammation,chronic obstructive pulmonary disease (COPD), colitis, dermatitis(including contact dermatitis and atopic dermatitis), diabetes,diverticulitis, endotoxic shock (septic shock), fibrosis, hidradenitissuppurativa, inflammatory bowel disease, Crohn's disease, intimalhyperplasia, localized inflammatory disease, lupus, morphea, orbitalinflammatory disease, Idiopathic Orbital Inflammatory Disease, pelvicinflammatory disease, psoriasis, Raynaud's disease/phenomenon,rheumatoid arthritis, osteoarthritis, scleroderma, Sjogren's syndrome,tendinopathy, transplant rejection, ulcers, vasculitis, andvasculopathy.